Transcriptional regulation by RUNX2 (Homo sapiens)

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8, 12, 15, 21, 26...56, 66, 91, 105, 11124, 30, 39, 49, 56...61, 1083913112873912761707689, 125108, 17249, 721213190833923, 35, 62, 145, 157...24, 5614310487398799, 13617069, 952131, 4973301022168, 99, 13668, 99, 1362474, 165741531193989, 12561, 108172567453165111nucleoplasmendoplasmic reticulum lumencytosolGLI3R p-S432-RUNX2:CBFBRUNX2:CBFBp-T,Y MAPK dimersRUNX2:CBFB:p-2S-SMAD1:p-2S-SMAD1:SMAD4p-S183,T185,T187-RUNX2-P2 Hedgehog 'off' statep-S196,T198,T200-RUNX2-P1 SMAD6 gene RUNX2-P1 RUNX2-P1 RUNX2-P2 RUNX2-P1 AR RUNX2-P2 TWIST2 RUNX2-P2 RUNX2:RB1:COL1A1geneMyrG-p-Y419-SRC RUNX2-P1 CCND1 RUNX2-P1 BGLAP geneRUNX2-P1 CBFB p-S280,S298-RUNX2-P2 RUNX2-P2 RUNX2-P2 p-S465-RUNX2-P1 LGALS3 geneCCND1:CDK42p-GLI2RUNX2-P2 RUNX2:WWTR1:BGLAPgenep-S465-RUNX2-P1 Signaling by NOTCH1RUNX2-P1 RUNX2:MAF:BGLAP geneRUNX2:CBFB:p-Y-YAP1RB1 UCMA gene RUNX2-P2 RUNX2-P1 p-S451-RUNX2:CBFBRBM14CBFB RUNX2:ZNF521:HDAC3RUNX2:SOX9Transcriptionalregulation by RUNX1PPM1DZNF521 RUNX2-P1 RUNX2-P1 RUNX2-P2 RUNX1 CBFBCBFB RB1 LGALS3 gene p-T202,Y204-MAPK3 RUNX2-P2 WWTR1 RUNX2:HDAC6RUNX2:HDAC4p-S280,S298-RUNX2-P2 HES1 RUNX2-P1 CDKN1ABMP2 RUNX2:HAND2RUNX2-P2 RUNX2-P2 CCNB1 COL1A1 gene CCNB1:p-T161-CDK1SMAD4 SP7SATB2 RUNX2-P2 RUNX1:CBFB:LGALS3geneRUNX2-P2 RUNX2-P2 SP7 HEY2 CBFB p-2S-SMAD1:p-2S-SMAD1:SMAD4RUNX2:HEY1,HEY2,HES1HES1 HAND2p-S432-RUNX2-P1 ATPMMP13 gene ATPMMP13 geneRUNX2-P2 p-S196,T198,T200-RUNX2:CBFBCBFB 2p-GLI2 ADPp-S451-RUNX2-P2 MAF p-S465-RUNX2-P1 RUNX2-P2 RUNX2:GLI3RBGLAP gene p-T308,S473-AKT1 6-Dehydrotestosterone RUNX2:AR:androgenp-S294,S312-RUNX2-P1 MAFCOL1A1 geneRUNX2-P1 p-Y-YAP1RUNX2:CBFB,p-S451-RUNX2:CBFB,(p-2S-RUNX2:CBFB)p-S451-RUNX2-P2 RUNX2:RB1p-S463,S465-SMAD1 CBFB SMAD6ADPp-S418-RUNX2-P2 CBFB RUNX2-P2 RUNX2-P2 p-S280,S298-RUNX2-P2 CBFB p-S451-RUNX2-P2 RUNX2-P1 UCMA geneRUNX2-P1 RUNX2-P2 BAX geneMyrG-p-Y426-YES1 MMP13p-Y-YAP1 p-Y-YAP1 androst-4-en-3,17-dione BGLAP gene ATPCBFB TWIST1 SOX9 HDAC6 RUNX2:CBFB:ITGA5geneRUNX2:CBFB,p-S451-RUNX2:CBFB,(p-2S-RUNX2:CBFB):BGLAP geneCBFB p-T185,Y187-MAPK1 HDAC3DHTEST RUNX2-P2 BGLAP gene p-S451-RUNX2-P2 p-S451-RUNX2-P2 SMAD4 HEY1 LGALS3RUNX2-P2 CBFB p-S196,T198,T200-RUNX2-P1 RUNX2-P1 RUNX2-P1 RUNX2-P2 RAF/MAP kinasecascadeMyrG-p-Y419-SRC,MyrG-p-Y426-YES1p-S463,S465-SMAD1 AR HEY2 Hedgehog 'on' stateRUNX2-P1 RUNX2-P2 HDAC6 RUNX2-P1 BGLAP gene RUNX2-P1 CBFB DHTEST TWIST2 RUNX2-P2 RUNX2-P1 RUNX2:CBFB:p-Y-YAP1:BGLAP geneYAP1RUNX2:CBFB:p-2S-SMAD1:p-2S-SMAD1:SMAD4:SMAD6 geneBMP2 dimerCOL1A1p-Y226,Y393-ABL1HEY1 RBM14 CDKN1A geneUCMAHDAC4 p-S465-RUNX2-P1 WWTR1 p-S463,S465-SMAD1 p-T305,S472-AKT3 H2OCBFB RUNX2-P1 CDKN1A gene CBFB SATB2IHH genep-Y-YAP1RUNX2-P1 p-S465-RUNX2-P1 RUNX2-P1 BGLAP(24-100)RUNX2:MAFRUNX2-P1 SMAD6 geneandrost-4-en-3,17-dione GLI3RATPRUNX2:CBFB:SP7:UCMAgeneZNF521p-S183,T185,T187-RUNX2-P2 CBFB AR:androgenCBFB HDAC6 WWTR1RUNX2-P2 RUNX2:RB1:BGLAP geneADPRegulation of RUNX2expression andactivityMAF ADPHDAC3 ITGBL1 gene p-S294,S312-RUNX2-P1 CBFB RUNX2-P1 PPiITGBL1 geneIHHRUNX2-P2 HDAC4ITGBL1RB1BGLAP gene RUNX2:CBFB:BAX geneRUNX2-P2 RUNX2-P1 RUNX2-P2 RUNX2-P1 RUNX2-P1 HAND2 CDK4 RUNX2:RBM14TEST ITGA5(42-894)RUNX2-P1 6-Dehydrotestosterone RUNX2:TWIST1,TWIST2RUNX2:SATB2HDAC6(p-S451-RUNX2:CBFB,RUNX2:CBFB,RUNX2:HDAC6)MyrG-p-Y419-SRC RUNX2-P1 ITGA5 gene RB1 p-2S-RUNX2:CBFBp-T,p-S-AKTYAP1 RUNX2-P1 CBFB BAXRUNX2-P2 SMAD4 RUNX2:CBFB:IHH geneRUNX2CBFB RUNX2:2p-GLI2RUNX2-P1 TEST LGALS3 gene p-S294,S312-RUNX2-P1 RUNX2-P2 CBFB SOX9MyrG-p-Y426-YES1 RUNX2-P1 RUNX2-P2 RUNX2:CBFB:LGALS3geneSignaling by BMPTWIST1 RUNX2:WWTR1(TAZ)HEY1,HEY2,HES1MyrG-p-Y419-SRC,MyrG-p-Y426-YES1:YAP1RUNX2-P2 RUNX2-P2 IHH gene ITGA5 geneRUNX2:CBFB:ITGBL1geneTWIST1,TWIST2RUNX2-P1 p-T161-CDK1 p-T309,S474-AKT2 RUNX2-P2 CBFB (p-S451-RUNX2:CBFB,RUNX2:CBFB,RUNX2:HDAC6):CDKN1A geneRUNX2-P2 p-S196,T198,T200-RUNX2:CBFB:MMP13 geneRUNX2-P1 BAX gene 39689, 25, 63, 1152, 1132410439168172219, 25, 63, 115127317217015390761251198712539124, 22, 40, 42, 43, 50...875691493, 8, 16, 35, 36, 46...10, 11, 18, 51, 70...1, 5-7, 13...


Description

RUNX2 (CBFA1 or AML3) transcription factor, similar to other RUNX family members, RUNX1 and RUNX3, can function in complex with CBFB (CBF-beta) (Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002). RUNX2 mainly regulates transcription of genes involved in skeletal development (reviewed in Karsenty 2008). RUNX2 is involved in development of both intramembraneous and endochondral bones through regulation of osteoblast differentiation and chondrocyte maturation, respectively. RUNX2 stimulates transcription of the BGLAP gene (Ducy and Karsenty 1995, Ducy et al. 1997), which encodes Osteocalcin, a bone-derived hormone which is one of the most abundant non-collagenous proteins of the bone extracellular matrix (reviewed in Karsenty and Olson 2016). RUNX2 directly controls the expression of most genes associated with osteoblast differentiation and function (Sato et al. 1998, Ducy et al. 1999, Roce et al. 2005). RUNX2-mediated transcriptional regulation of several genes involved in GPCR (G protein coupled receptor) signaling is implicated in the control of growth of osteoblast progenitors (Teplyuk et al. 2009). RUNX2 promotes chondrocyte maturation by stimulating transcription of the IHH gene, encoding Indian hedgehog (Takeda et al. 2001, Yoshida et al. 2004). Germline loss-of-function mutations of the RUNX2 gene are associated with cleidocranial dysplasia syndrome (CCD), an autosomal skeletal disorder (reviewed in Jaruga et al. 2016). The function of RUNX2 is frequently disrupted in osteosarcoma (reviewed in Mortus et al. 2014). Vitamin D3 is implicated in regulation of transcriptional activity of the RUNX2:CBFB complex (Underwood et al. 2012).

RUNX2 expression is regulated by estrogen signaling, and RUNX2 is implicated in breast cancer development and metastasis (reviewed in Wysokinski et al. 2014). Besides estrogen receptor alpha (ESR1) and estrogen-related receptor alpha (ERRA) (Kammerer et al. 2013), RUNX2 transcription is also regulated by TWIST1 (Yang, Yang et al. 2011), glucocorticoid receptor (NR3C1) (Zhang et al. 2012), NKX3-2 (BAPX1) (Tribioli and Lufkin 1999, Lengner et al. 2005), DLX5 (Robledo et al. 2002, Lee et al. 2005) and MSX2 (Lee et al. 2005). RUNX2 can autoregulate, by directly inhibiting its own transcription (Drissi et al. 2000). Several E3 ubiquitin ligases target RUNX2 for proteasome-mediated degradation: FBXW7a (Kumar et al. 2015), STUB1 (CHIP) (Li et al. 2008), SMURF1 (Zhao et al. 2003, Yang et al. 2014), WWP1 (Jones et al. 2006), and SKP2 (Thacker et al. 2016). Besides formation of RUNX2:CBFB heterodimers, transcriptional activity of RUNX2 is regulated by binding to a number of other transcription factors, for example SOX9 (Zhou et al. 2006, TWIST1 (Bialek et al. 2004) and RB1 (Thomas et al. 2001).<p>RUNX2 regulates expression of several genes implicated in cell migration during normal development and bone metastasis of breast cancer cells. RUNX2 stimulates transcription of the ITGA5 gene, encoding Integrin alpha 5 (Li et al. 2016) and the ITGBL1 gene, encoding Integrin beta like protein 1 (Li et al. 2015). RUNX2 mediated transcription of the MMP13 gene, encoding Colagenase 3 (Matrix metalloproteinase 13), is stimulated by AKT mediated phosphorylation of RUNX2 (Pande et al. 2013). RUNX2 is implicated in positive regulation of AKT signaling by stimulating expression of AKT-activating TORC2 complex components MTOR and RICTOR, which may contribute to survival of breast cancer cells (Tandon et al. 2014).<p>RUNX2 inhibits CDKN1A transcription, thus preventing CDKN1A-induced cell cycle arrest. Phosphorylation of RUNX2 by CDK4 in response to high glucose enhances RUNX2-mediated repression of the CDKN1A gene in endothelial cells (Pierce et al. 2012). In mice, Runx2-mediated repression of Cdkn1a may contribute to the development of acute myeloid leukemia (AML) (Kuo et al. 2009). RUNX2 can stimulate transcription of the LGALS3 gene, encoding Galectin-3 (Vladimirova et al. 2008, Zhang et al. 2009). Galectin 3 is expressed in myeloid progenitors and its levels increase during the maturation process (Le Marer 2000).<p>For a review of RUNX2 function, please refer to Long 2012 and Ito et al. 2015. View original pathway at Reactome.</div>

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Pathway is converted from Reactome ID: 8878166
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Reactome Author: Orlic-Milacic, Marija

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  78. Jones DC, Wein MN, Oukka M, Hofstaetter JG, Glimcher MJ, Glimcher LH.; ''Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3.''; PubMed Europe PMC Scholia
  79. Yang LT, Nichols JT, Yao C, Manilay JO, Robey EA, Weinmaster G.; ''Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1.''; PubMed Europe PMC Scholia
  80. Wysokinski D, Blasiak J, Pawlowska E.; ''Role of RUNX2 in Breast Carcinogenesis.''; PubMed Europe PMC Scholia
  81. Karsenty G, Olson EN.; ''Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication.''; PubMed Europe PMC Scholia
  82. Chastagner P, Israël A, Brou C.; ''AIP4/Itch regulates Notch receptor degradation in the absence of ligand.''; PubMed Europe PMC Scholia
  83. Funato N, Chapman SL, McKee MD, Funato H, Morris JA, Shelton JM, Richardson JA, Yanagisawa H.; ''Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2.''; PubMed Europe PMC Scholia
  84. Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, Karsenty G.; ''A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development.''; PubMed Europe PMC Scholia
  85. Keita M, Bachvarova M, Morin C, Plante M, Gregoire J, Renaud MC, Sebastianelli A, Trinh XB, Bachvarov D.; ''The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion.''; PubMed Europe PMC Scholia
  86. Shigesada K, van de Sluis B, Liu PP.; ''Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11.''; PubMed Europe PMC Scholia
  87. Wang Q, Wei X, Zhu T, Zhang M, Shen R, Xing L, O'Keefe RJ, Chen D.; ''Bone morphogenetic protein 2 activates Smad6 gene transcription through bone-specific transcription factor Runx2.''; PubMed Europe PMC Scholia
  88. Hu QD, Ang BT, Karsak M, Hu WP, Cui XY, Duka T, Takeda Y, Chia W, Sankar N, Ng YK, Ling EA, Maciag T, Small D, Trifonova R, Kopan R, Okano H, Nakafuku M, Chiba S, Hirai H, Aster JC, Schachner M, Pallen CJ, Watanabe K, Xiao ZC.; ''F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation.''; PubMed Europe PMC Scholia
  89. Vladimirova V, Waha A, Lückerath K, Pesheva P, Probstmeier R.; ''Runx2 is expressed in human glioma cells and mediates the expression of galectin-3.''; PubMed Europe PMC Scholia
  90. Shimoyama A, Wada M, Ikeda F, Hata K, Matsubara T, Nifuji A, Noda M, Amano K, Yamaguchi A, Nishimura R, Yoneda T.; ''Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function.''; PubMed Europe PMC Scholia
  91. Wee HJ, Huang G, Shigesada K, Ito Y.; ''Serine phosphorylation of RUNX2 with novel potential functions as negative regulatory mechanisms.''; PubMed Europe PMC Scholia
  92. Zhang L, Lukasik SM, Speck NA, Bushweller JH.; ''Structural and functional characterization of Runx1, CBF beta, and CBF beta-SMMHC.''; PubMed Europe PMC Scholia
  93. Tahirov TH, Inoue-Bungo T, Morii H, Fujikawa A, Sasaki M, Kimura K, Shiina M, Sato K, Kumasaka T, Yamamoto M, Ishii S, Ogata K.; ''Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta.''; PubMed Europe PMC Scholia
  94. Chen AI, de Nooij JC, Jessell TM.; ''Graded activity of transcription factor Runx3 specifies the laminar termination pattern of sensory axons in the developing spinal cord.''; PubMed Europe PMC Scholia
  95. Rajgopal A, Young DW, Mujeeb KA, Stein JL, Lian JB, van Wijnen AJ, Stein GS.; ''Mitotic control of RUNX2 phosphorylation by both CDK1/cyclin B kinase and PP1/PP2A phosphatase in osteoblastic cells.''; PubMed Europe PMC Scholia
  96. Baladrón V, Ruiz-Hidalgo MJ, Nueda ML, Díaz-Guerra MJ, García-Ramírez JJ, Bonvini E, Gubina E, Laborda J.; ''dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats.''; PubMed Europe PMC Scholia
  97. Matsuno K, Eastman D, Mitsiades T, Quinn AM, Carcanciu ML, Ordentlich P, Kadesch T, Artavanis-Tsakonas S.; ''Human deltex is a conserved regulator of Notch signalling.''; PubMed Europe PMC Scholia
  98. Li L, Milner LA, Deng Y, Iwata M, Banta A, Graf L, Marcovina S, Friedman C, Trask BJ, Hood L, Torok-Storb B.; ''The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1.''; PubMed Europe PMC Scholia
  99. Goloudina AR, Mazur SJ, Appella E, Garrido C, Demidov ON.; ''Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-xL ratio.''; PubMed Europe PMC Scholia
  100. Kammerer M, Gutzwiller S, Stauffer D, Delhon I, Seltenmeyer Y, Fournier B.; ''Estrogen Receptor α (ERα) and Estrogen Related Receptor α (ERRα) are both transcriptional regulators of the Runx2-I isoform.''; PubMed Europe PMC Scholia
  101. Fryer CJ, White JB, Jones KA.; ''Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.''; PubMed Europe PMC Scholia
  102. Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, Wu H, Yu K, Ornitz DM, Olson EN, Justice MJ, Karsenty G.; ''A twist code determines the onset of osteoblast differentiation.''; PubMed Europe PMC Scholia
  103. Leimeister C, Schumacher N, Steidl C, Gessler M.; ''Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos.''; PubMed Europe PMC Scholia
  104. Zhou G, Zheng Q, Engin F, Munivez E, Chen Y, Sebald E, Krakow D, Lee B.; ''Dominance of SOX9 function over RUNX2 during skeletogenesis.''; PubMed Europe PMC Scholia
  105. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G.; ''Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation.''; PubMed Europe PMC Scholia
  106. Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M.; ''The Notch target genes Hey1 and Hey2 are required for embryonic vascular development.''; PubMed Europe PMC Scholia
  107. Robledo RF, Rajan L, Li X, Lufkin T.; ''The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development.''; PubMed Europe PMC Scholia
  108. Calo E, Quintero-Estades JA, Danielian PS, Nedelcu S, Berman SD, Lees JA.; ''Rb regulates fate choice and lineage commitment in vivo.''; PubMed Europe PMC Scholia
  109. Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, Chui I, Deshaies RJ, Kitajewski J.; ''SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation.''; PubMed Europe PMC Scholia
  110. Eiraku M, Tohgo A, Ono K, Kaneko M, Fujishima K, Hirano T, Kengaku M.; ''DNER acts as a neuron-specific Notch ligand during Bergmann glial development.''; PubMed Europe PMC Scholia
  111. Ge C, Xiao G, Jiang D, Yang Q, Hatch NE, Roca H, Franceschi RT.; ''Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor.''; PubMed Europe PMC Scholia
  112. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
  113. Goumans MJ, Zwijsen A, Ten Dijke P, Bailly S.; ''Bone Morphogenetic Proteins in Vascular Homeostasis and Disease.''; PubMed Europe PMC Scholia
  114. Wallberg AE, Pedersen K, Lendahl U, Roeder RG.; ''p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro.''; PubMed Europe PMC Scholia
  115. Ingham PW, Nakano Y, Seger C.; ''Mechanisms and functions of Hedgehog signalling across the metazoa.''; PubMed Europe PMC Scholia
  116. Hartmann D, de Strooper B, Serneels L, Craessaerts K, Herreman A, Annaert W, Umans L, Lübke T, Lena Illert A, von Figura K, Saftig P.; ''The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts.''; PubMed Europe PMC Scholia
  117. Tribioli C, Lufkin T.; ''The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen.''; PubMed Europe PMC Scholia
  118. van Tetering G, van Diest P, Verlaan I, van der Wall E, Kopan R, Vooijs M.; ''Metalloprotease ADAM10 is required for Notch1 site 2 cleavage.''; PubMed Europe PMC Scholia
  119. Li X, Hoeppner LH, Jensen ED, Gopalakrishnan R, Westendorf JJ.; ''Co-activator activator (CoAA) prevents the transcriptional activity of Runt domain transcription factors.''; PubMed Europe PMC Scholia
  120. Wang X, Blagden C, Fan J, Nowak SJ, Taniuchi I, Littman DR, Burden SJ.; ''Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle.''; PubMed Europe PMC Scholia
  121. Friedman AD.; ''Cell cycle and developmental control of hematopoiesis by Runx1.''; PubMed Europe PMC Scholia
  122. Kobayashi A, Senzaki K, Ozaki S, Yoshikawa M, Shiga T.; ''Runx1 promotes neuronal differentiation in dorsal root ganglion.''; PubMed Europe PMC Scholia
  123. Sato M, Morii E, Komori T, Kawahata H, Sugimoto M, Terai K, Shimizu H, Yasui T, Ogihara H, Yasui N, Ochi T, Kitamura Y, Ito Y, Nomura S.; ''Transcriptional regulation of osteopontin gene in vivo by PEBP2alphaA/CBFA1 and ETS1 in the skeletal tissues.''; PubMed Europe PMC Scholia
  124. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U, Bondesson M.; ''Hypoxia requires notch signaling to maintain the undifferentiated cell state.''; PubMed Europe PMC Scholia
  125. Zhang HY, Jin L, Stilling GA, Ruebel KH, Coonse K, Tanizaki Y, Raz A, Lloyd RV.; ''RUNX1 and RUNX2 upregulate Galectin-3 expression in human pituitary tumors.''; PubMed Europe PMC Scholia
  126. Chimge NO, Frenkel B.; ''The RUNX family in breast cancer: relationships with estrogen signaling.''; PubMed Europe PMC Scholia
  127. Lai EC, Deblandre GA, Kintner C, Rubin GM.; ''Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta.''; PubMed Europe PMC Scholia
  128. Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israël A.; ''A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.''; PubMed Europe PMC Scholia
  129. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R.; ''A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.''; PubMed Europe PMC Scholia
  130. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia
  131. Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K, Inoue K, Yamana K, Zanma A, Takada K, Ito Y, Komori T.; ''Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog.''; PubMed Europe PMC Scholia
  132. Jaruga A, Hordyjewska E, Kandzierski G, Tylzanowski P.; ''Cleidocranial dysplasia and RUNX2-clinical phenotype-genotype correlation.''; PubMed Europe PMC Scholia
  133. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  134. Koo BK, Yoon MJ, Yoon KJ, Im SK, Kim YY, Kim CH, Suh PG, Jan YN, Kong YY.; ''An obligatory role of mind bomb-1 in notch signaling of mammalian development.''; PubMed Europe PMC Scholia
  135. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  136. Goloudina AR, Tanoue K, Hammann A, Fourmaux E, Le Guezennec X, Bulavin DV, Mazur SJ, Appella E, Garrido C, Demidov ON.; ''Wip1 promotes RUNX2-dependent apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents.''; PubMed Europe PMC Scholia
  137. Li X, Huang M, Zheng H, Wang Y, Ren F, Shang Y, Zhai Y, Irwin DM, Shi Y, Chen D, Chang Z.; ''CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation.''; PubMed Europe PMC Scholia
  138. Maier MM, Gessler M.; ''Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes.''; PubMed Europe PMC Scholia
  139. Ito Y, Bae SC, Chuang LS.; ''The RUNX family: developmental regulators in cancer.''; PubMed Europe PMC Scholia
  140. Ichikawa M, Yoshimi A, Nakagawa M, Nishimoto N, Watanabe-Okochi N, Kurokawa M.; ''A role for RUNX1 in hematopoiesis and myeloid leukemia.''; PubMed Europe PMC Scholia
  141. Koo BK, Yoon KJ, Yoo KW, Lim HS, Song R, So JH, Kim CH, Kong YY.; ''Mind bomb-2 is an E3 ligase for Notch ligand.''; PubMed Europe PMC Scholia
  142. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
  143. Vega RB, Matsuda K, Oh J, Barbosa AC, Yang X, Meadows E, McAnally J, Pomajzl C, Shelton JM, Richardson JA, Karsenty G, Olson EN.; ''Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis.''; PubMed Europe PMC Scholia
  144. Roca H, Phimphilai M, Gopalakrishnan R, Xiao G, Franceschi RT.; ''Cooperative interactions between RUNX2 and homeodomain protein-binding sites are critical for the osteoblast-specific expression of the bone sialoprotein gene.''; PubMed Europe PMC Scholia
  145. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ.; ''Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development.''; PubMed Europe PMC Scholia
  146. Bäckström S, Wolf-Watz M, Grundström C, Härd T, Grundström T, Sauer UH.; ''The RUNX1 Runt domain at 1.25A resolution: a structural switch and specifically bound chloride ions modulate DNA binding.''; PubMed Europe PMC Scholia
  147. Mortus JR, Zhang Y, Hughes DP.; ''Developmental pathways hijacked by osteosarcoma.''; PubMed Europe PMC Scholia
  148. Zhao X, Chen A, Yan X, Zhang Y, He F, Hayashi Y, Dong Y, Rao Y, Li B, Conway RM, Maiques-Diaz A, Elf SE, Huang N, Zuber J, Xiao Z, Tse W, Tenen DG, Wang Q, Chen W, Mulloy JC, Nimer SD, Huang G.; ''Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal.''; PubMed Europe PMC Scholia
  149. Koutelou E, Sato S, Tomomori-Sato C, Florens L, Swanson SK, Washburn MP, Kokkinaki M, Conaway RC, Conaway JW, Moschonas NK.; ''Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1.''; PubMed Europe PMC Scholia
  150. Kanno T, Kanno Y, Chen LF, Ogawa E, Kim WY, Ito Y.; ''Intrinsic transcriptional activation-inhibition domains of the polyomavirus enhancer binding protein 2/core binding factor alpha subunit revealed in the presence of the beta subunit.''; PubMed Europe PMC Scholia
  151. Takeda S, Bonnamy JP, Owen MJ, Ducy P, Karsenty G.; ''Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice.''; PubMed Europe PMC Scholia
  152. Boller S, Grosschedl R.; ''The regulatory network of B-cell differentiation: a focused view of early B-cell factor 1 function.''; PubMed Europe PMC Scholia
  153. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D.; ''Mutations in NOTCH1 cause aortic valve disease.''; PubMed Europe PMC Scholia
  154. Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U.; ''The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog.''; PubMed Europe PMC Scholia
  155. Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA.; ''Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex.''; PubMed Europe PMC Scholia
  156. Chen CL, Broom DC, Liu Y, de Nooij JC, Li Z, Cen C, Samad OA, Jessell TM, Woolf CJ, Ma Q.; ''Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.''; PubMed Europe PMC Scholia
  157. Otto F, Kanegane H, Mundlos S.; ''Mutations in the RUNX2 gene in patients with cleidocranial dysplasia.''; PubMed Europe PMC Scholia
  158. Teplyuk NM, Galindo M, Teplyuk VI, Pratap J, Young DW, Lapointe D, Javed A, Stein JL, Lian JB, Stein GS, van Wijnen AJ.; ''Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors.''; PubMed Europe PMC Scholia
  159. Ichikawa M, Asai T, Chiba S, Kurokawa M, Ogawa S.; ''Runx1/AML-1 ranks as a master regulator of adult hematopoiesis.''; PubMed Europe PMC Scholia
  160. Lee MH, Kim YJ, Yoon WJ, Kim JI, Kim BG, Hwang YS, Wozney JM, Chi XZ, Bae SC, Choi KY, Cho JY, Choi JY, Ryoo HM.; ''Dlx5 specifically regulates Runx2 type II expression by binding to homeodomain-response elements in the Runx2 distal promoter.''; PubMed Europe PMC Scholia
  161. Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams RH.; ''The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis.''; PubMed Europe PMC Scholia
  162. Shimizu K, Chiba S, Saito T, Kumano K, Hirai H.; ''Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors.''; PubMed Europe PMC Scholia
  163. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
  164. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD.; ''SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.''; PubMed Europe PMC Scholia
  165. Westendorf JJ, Zaidi SK, Cascino JE, Kahler R, van Wijnen AJ, Lian JB, Yoshida M, Stein GS, Li X.; ''Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter.''; PubMed Europe PMC Scholia
  166. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
  167. Rhyu MS, Jan LY, Jan YN.; ''Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells.''; PubMed Europe PMC Scholia
  168. Kundu M, Javed A, Jeon JP, Horner A, Shum L, Eckhaus M, Muenke M, Lian JB, Yang Y, Nuckolls GH, Stein GS, Liu PP.; ''Cbfbeta interacts with Runx2 and has a critical role in bone development.''; PubMed Europe PMC Scholia
  169. Wu D, Ozaki T, Yoshihara Y, Kubo N, Nakagawara A.; ''Runt-related transcription factor 1 (RUNX1) stimulates tumor suppressor p53 protein in response to DNA damage through complex formation and acetylation.''; PubMed Europe PMC Scholia
  170. Lee YJ, Park SY, Lee SJ, Boo YC, Choi JY, Kim JE.; ''Ucma, a direct transcriptional target of Runx2 and Osterix, promotes osteoblast differentiation and nodule formation.''; PubMed Europe PMC Scholia
  171. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC Scholia
  172. Thomas DM, Carty SA, Piscopo DM, Lee JS, Wang WF, Forrester WC, Hinds PW.; ''The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114647view16:11, 25 January 2021ReactomeTeamReactome version 75
113095view11:15, 2 November 2020ReactomeTeamReactome version 74
112329view15:25, 9 October 2020ReactomeTeamReactome version 73
101722view16:25, 1 November 2018DeSlOntology Term : 'regulatory pathway' added !
101228view11:12, 1 November 2018ReactomeTeamreactome version 66
100766view20:38, 31 October 2018ReactomeTeamreactome version 65
100310view19:15, 31 October 2018ReactomeTeamreactome version 64
99856view15:59, 31 October 2018ReactomeTeamreactome version 63
99820view15:21, 31 October 2018ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
(p-S451-RUNX2:CBFB,RUNX2:CBFB,RUNX2:HDAC6):CDKN1A geneComplexR-HSA-9008444 (Reactome)
(p-S451-RUNX2:CBFB,RUNX2:CBFB,RUNX2:HDAC6)ComplexR-HSA-9008443 (Reactome)
2p-GLI2 ProteinP10070 (Uniprot-TrEMBL)
2p-GLI2ProteinP10070 (Uniprot-TrEMBL)
6-Dehydrotestosterone MetaboliteCHEBI:29117 (ChEBI)
ADPMetaboliteCHEBI:456216 (ChEBI)
AR ProteinP10275 (Uniprot-TrEMBL)
AR:androgenComplexR-HSA-5618087 (Reactome)
ATPMetaboliteCHEBI:30616 (ChEBI)
BAX gene ProteinENSG00000087088 (Ensembl)
BAX geneGeneProductENSG00000087088 (Ensembl)
BAXProteinQ07812 (Uniprot-TrEMBL)
BGLAP gene ProteinENSG00000242252 (Ensembl)
BGLAP geneGeneProductENSG00000242252 (Ensembl)
BGLAP(24-100)ProteinP02818 (Uniprot-TrEMBL)
BMP2 ProteinP12643 (Uniprot-TrEMBL)
BMP2 dimerComplexR-HSA-201463 (Reactome)
CBFB ProteinQ13951 (Uniprot-TrEMBL)
CBFBProteinQ13951 (Uniprot-TrEMBL)
CCNB1 ProteinP14635 (Uniprot-TrEMBL)
CCNB1:p-T161-CDK1ComplexR-HSA-170160 (Reactome)
CCND1 ProteinP24385 (Uniprot-TrEMBL)
CCND1:CDK4ComplexR-HSA-113844 (Reactome)
CDK4 ProteinP11802 (Uniprot-TrEMBL)
CDKN1A gene ProteinENSG00000124762 (Ensembl)
CDKN1A geneGeneProductENSG00000124762 (Ensembl)
CDKN1AProteinP38936 (Uniprot-TrEMBL)
COL1A1 gene ProteinENSG00000108821 (Ensembl)
COL1A1 geneGeneProductENSG00000108821 (Ensembl)
COL1A1ProteinP02452 (Uniprot-TrEMBL)
DHTEST MetaboliteCHEBI:16330 (ChEBI)
GLI3R ProteinP10071 (Uniprot-TrEMBL)
GLI3RProteinP10071 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HAND2 ProteinP61296 (Uniprot-TrEMBL)
HAND2ProteinP61296 (Uniprot-TrEMBL)
HDAC3 ProteinO15379 (Uniprot-TrEMBL)
HDAC3ProteinO15379 (Uniprot-TrEMBL)
HDAC4 ProteinP56524 (Uniprot-TrEMBL)
HDAC4ProteinP56524 (Uniprot-TrEMBL)
HDAC6 ProteinQ9UBN7 (Uniprot-TrEMBL)
HDAC6ProteinQ9UBN7 (Uniprot-TrEMBL)
HES1 ProteinQ14469 (Uniprot-TrEMBL)
HEY1 ProteinQ9Y5J3 (Uniprot-TrEMBL)
HEY1,HEY2,HES1ComplexR-HSA-9008192 (Reactome)
HEY2 ProteinQ9UBP5 (Uniprot-TrEMBL)
Hedgehog 'off' statePathwayR-HSA-5610787 (Reactome) Hedgehog is a secreted morphogen that has evolutionarily conserved roles in body organization by regulating the activity of the Ci/Gli transcription factor family. In Drosophila in the absence of Hh signaling, full-length Ci is partially degraded by the proteasome to generate a truncated repressor form that translocates to the nucleus to represses Hh-responsive genes. Binding of Hh ligand to the Patched (PTC) receptor allows the 7-pass transmembrane protein Smoothened (SMO) to be activated in an unknown manner, disrupting the partial proteolysis of Ci and allowing the full length activator form to accumulate (reviewed in Ingham et al, 2011; Briscoe and Therond, 2013).
While many of the core components of Hh signaling are conserved from flies to humans, the pathways do show points of significant divergence. Notably, the human genome encodes three Ci homologues, GLI1, 2 and 3 that each play slightly different roles in regulating Hh responsive genes. GLI3 is the primary repressor of Hh signaling in vertebrates, and is converted to the truncated GLI3R repressor form in the absence of Hh. GLI2 is a potent activator of transcription in the presence of Hh but contributes only minimally to the repression function. While a minor fraction of GLI2 protein is processed into the repressor form in the absence of Hh, the majority is either fully degraded by the proteasome or sequestered in the full-length form in the cytosol by protein-protein interactions. GLI1 lacks the repression domain and appears to be an obligate transcriptional activator (reviewed in Briscoe and Therond, 2013).
Vertebrate but not fly Hh signaling also depends on the movement of pathway components through the primary cilium. The primary cilium is a non-motile microtubule based structure whose construction and maintenance depends on intraflagellar transport (IFT). Anterograde IFT moves molecules from the ciliary base along the axoneme to the ciliary tip in a manner that requires the microtubule-plus-end directed kinesin KIF3 motor complex and the IFT-B protein complex, while retrograde IFT back to the ciliary base depends on the minus-end directed dynein motor and the IFT-A complex. Genetic screens have identified a number of cilia-related proteins that are required both to maintain Hh in the 'off' state and to transduce the signal when the pathway is activated (reviewed in Hui and Angers, 2011; Goetz and Anderson, 2010).
Hedgehog 'on' statePathwayR-HSA-5632684 (Reactome) Hedgehog is a secreted morphogen that has evolutionarily conserved roles in body organization by regulating the activity of the Ci/Gli transcription factor family. In Drosophila in the absence of Hh signaling, full-length Ci is partially degraded by the proteasome to generate a truncated repressor form that translocates to the nucleus to represses Hh-responsive genes. Binding of Hh ligand to the Patched (PTC) receptor allows the 7-pass transmembrane protein Smoothened (SMO) to be activated in an unknown manner, disrupting the partial proteolysis of Ci and allowing the full length activator form to accumulate (reviewed in Ingham et al, 2011; Briscoe and Therond, 2013).
While many of the core components of Hh signaling are conserved from flies to humans, the pathways do show points of significant divergence. Notably, the human genome encodes three Ci homologues, GLI1, 2 and 3 that each play slightly different roles in regulating Hh responsive genes. GLI3 is the primary repressor of Hh signaling in vertebrates, and is converted to the truncated GLI3R repressor form in the absence of Hh. GLI2 is a potent activator of transcription in the presence of Hh but contributes only minimally to the repression function. While a minor fraction of GLI2 protein is processed into the repressor form in the absence of Hh, the majority is either fully degraded by the proteasome or sequestered in the full-length form in the cytosol by protein-protein interactions. GLI1 lacks the repression domain and appears to be an obligate transcriptional activator (reviewed in Briscoe and Therond, 2013).
Vertebrate but not fly Hh signaling also depends on the movement of pathway components through the primary cilium. The primary cilium is a non-motile microtubule based structure whose construction and maintenance depends on intraflagellar transport (IFT). Anterograde IFT moves molecules from the ciliary base along the axoneme to the ciliary tip in a manner that requires the microtubule-plus-end directed kinesin KIF3 motor complex and the IFT-B protein complex, while retrograde IFT back to the ciliary base depends on the minus-end directed dynein motor and the IFT-A complex. Genetic screens have identified a number of cilia-related proteins that are required both to maintain Hh in the 'off' state and to transduce the signal when the pathway is activated (reviewed in Hui and Angers, 2011; Goetz and Anderson, 2010).
IHH gene ProteinENSG00000163501 (Ensembl)
IHH geneGeneProductENSG00000163501 (Ensembl)
IHHProteinQ14623 (Uniprot-TrEMBL)
ITGA5 gene ProteinENSG00000161638 (Ensembl)
ITGA5 geneGeneProductENSG00000161638 (Ensembl)
ITGA5(42-894)ProteinP08648 (Uniprot-TrEMBL)
ITGBL1 gene ProteinENSG00000198542 (Ensembl)
ITGBL1 geneGeneProductENSG00000198542 (Ensembl)
ITGBL1ProteinO95965 (Uniprot-TrEMBL)
LGALS3 gene ProteinENSG00000131981 (Ensembl)
LGALS3 geneGeneProductENSG00000131981 (Ensembl)
LGALS3ProteinP17931 (Uniprot-TrEMBL)
MAF ProteinO75444 (Uniprot-TrEMBL)
MAFProteinO75444 (Uniprot-TrEMBL)
MMP13 gene ProteinENSG00000137745 (Ensembl)
MMP13 geneGeneProductENSG00000137745 (Ensembl)
MMP13ProteinP45452 (Uniprot-TrEMBL)
MyrG-p-Y419-SRC ProteinP12931 (Uniprot-TrEMBL)
MyrG-p-Y419-SRC,MyrG-p-Y426-YES1:YAP1ComplexR-HSA-8937821 (Reactome)
MyrG-p-Y419-SRC,MyrG-p-Y426-YES1ComplexR-HSA-8937825 (Reactome)
MyrG-p-Y426-YES1 ProteinP07947 (Uniprot-TrEMBL)
PPM1DProteinO15297 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RB1 ProteinP06400 (Uniprot-TrEMBL)
RB1ProteinP06400 (Uniprot-TrEMBL)
RBM14 ProteinQ96PK6 (Uniprot-TrEMBL)
RBM14ProteinQ96PK6 (Uniprot-TrEMBL)
RUNX1 ProteinQ01196 (Uniprot-TrEMBL)
RUNX1:CBFB:LGALS3 geneComplexR-HSA-8938391 (Reactome)
RUNX2-P1 ProteinQ13950-1 (Uniprot-TrEMBL)
RUNX2-P2 ProteinQ13950-2 (Uniprot-TrEMBL)
RUNX2:2p-GLI2ComplexR-HSA-8986298 (Reactome)
RUNX2:AR:androgenComplexR-HSA-8877906 (Reactome)
RUNX2:CBFB,p-S451-RUNX2:CBFB,(p-2S-RUNX2:CBFB):BGLAP geneComplexR-HSA-9008882 (Reactome)
RUNX2:CBFB,p-S451-RUNX2:CBFB,(p-2S-RUNX2:CBFB)ComplexR-HSA-9008881 (Reactome)
RUNX2:CBFB:BAX geneComplexR-HSA-9008858 (Reactome)
RUNX2:CBFB:IHH geneComplexR-HSA-8878255 (Reactome)
RUNX2:CBFB:ITGA5 geneComplexR-HSA-8939664 (Reactome)
RUNX2:CBFB:ITGBL1 geneComplexR-HSA-8939834 (Reactome)
RUNX2:CBFB:LGALS3 geneComplexR-HSA-8938367 (Reactome)
RUNX2:CBFB:SP7:UCMA geneComplexR-HSA-8939856 (Reactome)
RUNX2:CBFB:p-2S-SMAD1:p-2S-SMAD1:SMAD4:SMAD6 geneComplexR-HSA-8878016 (Reactome)
RUNX2:CBFB:p-2S-SMAD1:p-2S-SMAD1:SMAD4ComplexR-HSA-8877936 (Reactome)
RUNX2:CBFB:p-Y-YAP1:BGLAP geneComplexR-HSA-8937871 (Reactome)
RUNX2:CBFB:p-Y-YAP1ComplexR-HSA-8937863 (Reactome)
RUNX2:CBFBComplexR-HSA-8865420 (Reactome)
RUNX2:GLI3RComplexR-HSA-9008227 (Reactome)
RUNX2:HAND2ComplexR-HSA-9007811 (Reactome)
RUNX2:HDAC4ComplexR-HSA-9008328 (Reactome)
RUNX2:HDAC6ComplexR-HSA-9008392 (Reactome)
RUNX2:HEY1,HEY2,HES1ComplexR-HSA-9008188 (Reactome)
RUNX2:MAF:BGLAP geneComplexR-HSA-8877917 (Reactome)
RUNX2:MAFComplexR-HSA-8984995 (Reactome)
RUNX2:RB1:BGLAP geneComplexR-HSA-8985483 (Reactome)
RUNX2:RB1:COL1A1 geneComplexR-HSA-8985630 (Reactome)
RUNX2:RB1ComplexR-HSA-8985470 (Reactome)
RUNX2:RBM14ComplexR-HSA-8938353 (Reactome)
RUNX2:SATB2ComplexR-HSA-8985281 (Reactome)
RUNX2:SOX9ComplexR-HSA-8985335 (Reactome)
RUNX2:TWIST1,TWIST2ComplexR-HSA-9007857 (Reactome)
RUNX2:WWTR1(TAZ)ComplexR-HSA-2064919 (Reactome)
RUNX2:WWTR1:BGLAP geneComplexR-HSA-8985224 (Reactome)
RUNX2:ZNF521:HDAC3ComplexR-HSA-9008155 (Reactome)
RUNX2ComplexR-HSA-9007751 (Reactome)
Regulation of RUNX2

expression and

activity
PathwayR-HSA-8939902 (Reactome) Several transcription factors have been implicated in regulation of the RUNX2 gene transcription. Similar to the RUNX1 gene, the RUNX2 gene expression can be regulated from the proximal P2 promoter or the distal P1 promoter (reviewed in Li and Xiao 2007).
Activated estrogen receptor alpha (ESR1) binds estrogen response elements (EREs) in the P2 promoter and stimulates RUNX2 transcription (Kammerer et al. 2013). Estrogen-related receptor alpha (ERRA) binds EREs or estrogen-related response elements (ERREs) in the P2 promoter of RUNX2. When ERRA is bound to its co-factor PPARG1CA (PGC1A), it stimulates RUNX2 transcription. When bound to its co-factor PPARG1CB (PGC1B), ERRA represses RUNX2 transcription (Kammerer et al. 2013).
TWIST1, a basic helix-loop-helix (bHLH) transcription factor, stimulates RUNX2 transcription by binding to the E1-box in the P2 promoter (Yang, Yang et al. 2011). TWIST proteins also interact with the DNA-binding domain of RUNX2 to modulate its activity during skeletogenesis (Bialek et al. 2004). Schnurri-3 (SHN3) is another protein that interacts with RUNX2 to decrease its availability in the nucleus and therefore its activity (Jones et al. 2006). In contrast, RUNX2 and SATB2 interact to enhance the expression of osteoblast-specific genes (Dobreva et al. 2006). Formation of the heterodimer with CBFB (CBF-beta) also enhances the transcriptional activity of RUNX2 (Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002).
Transcription of RUNX2 from the proximal promoter is inhibited by binding of the glucocorticoid receptor (NR3C1) activated by dexamethasone (DEXA) to a glucocorticoid receptor response element (GRE), which is also present in the human promoter (Zhang et al. 2012).
NKX3-2 (BAPX1), required for embryonic development of the axial skeleton (Tribioli and Lufkin 1999), binds the distal (P1) promoter of the RUNX2 gene and inhibits its transcription (Lengner et al. 2005). RUNX2-P1 transcription is also autoinhibited by RUNX2-P1, which binds to RUNX2 response elements in the P1 promoter of RUNX2 (Drissi et al. 2000). In contrast, binding of RUNX2-P2 to the proximal P2 promoter autoactivates transcription of RUNX2-P2 (Ducy et al. 1999). Binding of a homeodomain transcription factor DLX5, and possibly DLX6, to the RUNX2 P1 promoter stimulates RUNX2 transcription (Robledo et al. 2002, Lee et al. 2005). The homeobox transcription factor MSX2 can bind to DLX5 sites in the promoter of RUNX2 and inhibit transcription of RUNX2-P1 (Lee et al. 2005).
Translocation of RUNX2 protein to the nucleus is inhibited by binding to non-activated STAT1 (Kim et al. 2003).
Several E3 ubiquitin ligases were shown to polyubiquitinate RUNX2, targeting it for proteasome-mediated degradation: FBXW7a (Kumar et al. 2015), STUB1 (CHIP) (Li et al. 2008), SMURF1 (Zhao et al. 2003, Yang et al. 2014), WWP1 (Jones et al. 2006), and SKP2 (Thacker et al. 2016).
SATB2 ProteinQ9UPW6 (Uniprot-TrEMBL)
SATB2ProteinQ9UPW6 (Uniprot-TrEMBL)
SMAD4 ProteinQ13485 (Uniprot-TrEMBL)
SMAD6 gene ProteinENSG00000137834 (Ensembl)
SMAD6 geneGeneProductENSG00000137834 (Ensembl)
SMAD6ProteinO43541 (Uniprot-TrEMBL)
SOX9 ProteinP48436 (Uniprot-TrEMBL)
SOX9ProteinP48436 (Uniprot-TrEMBL)
SP7 ProteinQ8TDD2 (Uniprot-TrEMBL)
SP7ProteinQ8TDD2 (Uniprot-TrEMBL)
Signaling by BMPPathwayR-HSA-201451 (Reactome) Bone morphogenetic proteins (BMPs) have many biological activities in various tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. They are members of the Transforming growth factor-Beta (TGFB) family. They bind to type II and type I serine-threonine kinase receptors, which transduce signals through SMAD and non-SMAD signalling pathways. BMP signalling is linked to a wide variety of clinical disorders, including vascular diseases, skeletal diseases and cancer. BMPs typically activate BMP type I receptors and signal via SMAD1, 5 and 8. They can be classified into several subgroups, including the BMP2/4 group, the BMP5-8 osteogenic protein-1 (OP1) group, the growth and differentiation factor (GDF) 5-7 group and the BMP9/10 group. Most of the proteins of the BMP2/4, OP1 and BMP9/10 groups induce formation of bone and cartilage tissues in vivo, while the GDF5-7 group induce cartilage and tendon-like, but not bone-like, tissues (Miyazono et al. 2010). Members of the TGFB family bind to two types of serine-threonine kinase receptors, type I and type II (Massagué 2012). BMPs can bind type I receptors in the absence of type II receptors, but both types are required for signal transduction. The presence of both types dramatically increases binding affinity (Rozenweig et al. 1995). The type II receptor kinase transphosphorylates the type I receptor, which transmits specific intracellular signals. Type I and type II receptors share similar structural properties, comprised of a relatively short extracellular domain, a single membrane-spanning domain and an intracellular domain containing a serine-threonine kinase domain. Seven receptors, collectively referred to as the Activin receptor-like kinases (ALK), have been identified as type I receptors for the TGFB family in mammals. ALKs are classified into three groups based on their structure and function, the BMPRI group (Bone morphogenetic protein receptor type-1A, ALK3, BMPR1A and Bone morphogenetic protein receptor type-1B, ALK6, BMPR1B), the ALK1 group (Serine/threonine-protein kinase receptor R3, ALK1, ACVRL1 and Activin receptor type-1, ALK2, ACVR1) and the TBetaR1 group (Activin receptor type-1B, ALK4, ACVR1B and TGF-beta receptor type-1, ALK5, TGFBR1 and Activin receptor type-1C, ALK7, ACVR1C) (Kawabata et al. 1998). ALK1 group and BMPRI group activate SMAD1/5/8 and transduce similar intracellular signals. The TBetaR1 group activate SMAD2/3. BMPR1A and ACVR1 are widely expressed. BMPR1B shows a more restricted expression profile. ACVRL1 is limited to endothelial cells and a few other cell types. The binding specificities of BMPs to type I receptors is affected by the type II receptors that are present (Yu et al. 2005). Typically, BMP2 and BMP4 bind to BMPR1A and BMPR1B (ten Dijke et al. 1994). BMP6 and BMP7 bind strongly to ACVR1 and weakly to BMPR1B. Growth/differentiation factor 5 (BMP14, GDF5) preferentially binds to BMPR1B, but not to other type I receptors (Nishitoh et al. 1995). BMP9 and BMP10 bind to ACVRL1 and ACVRL (Scharpfenecker et al. 2007). BMP type I receptors are shared by other members of the TGFB family. Three receptors, Bone morphogenetic protein receptor type-2 (BMPR2), Activin receptor type-2A (ACVR2A) and Activin receptor type-2B (ACVR2B) are the type II receptors for mammalian BMPs. They are widely expressed in various tissues. BMPR2 is specific for BMPs, whereas ACVR2A and ACVR2B are shared with activins and myostatin. BMP binding and signalling can be affected by coreceptors. Glycosylphosphatidylinositol (GPI)-anchored proteins of the repulsive guidance molecule (RGM) family, including RGMA, RGMB (DRAGON) and Hemojuvelin (HFE2, RGMC) are coreceptors for BMP2 and BMP4, enhancing signaling (Samad et al. 2005, Babitt et al. 2005, 2006). They interact with BMP type I and/or type II receptors and bind BMP2 and BMP4, but not BMP7 or TGFB1. BMP2/4 signalling normally involves BMPR2, not ACVR2A or ACVR2B. Cells transfected with RGMA use both BMPR2 and ACVR2A for BMP-2/4 signalling, suggesting that RGMA facilitates the use of ACVR2A by BMP2/4 (Xia et al. 2007). Endoglin (ENG) is a transmembrane protein expressed in proliferating endothelial cells. It binds various ligands including TGFB1/3, Activin-A and BMP2/7 (Barbara et al. 1999). It inhibits TGFB-induced responses and enhances BMP7-induced responses (Scherner et al. 2007). Mutations in ENG result in hereditary haemorrhagic telangiectasia (HHT1), also known as OslerWeberRendu disease, while mutations in ACVRL1 lead to HHT2, suggesting that they act in a common signalling pathway (McAllister et al. 1994, Johnson et al. 1996). BMP2 is a dimeric protein, having two receptor-binding motifs. One is a high-affinity binding site for BMPR1A, the other is a low-affinity binding site for BMPR2 (Kirsch et al. 2000). In the absence of ligand stimulation, small fractions of type II and type I receptors are present as preexisting homodimers and heterodimers on the cell surface. Ligand-binding increases oligomerization. The intracellular domains of type I receptors have a characteristic GS domain (glycine and serine-rich domain) located N-terminal to the serine-threonine kinase domains. Type II receptor kinases are constitutively active in the absence of ligand. Upon ligand binding, the type II receptor kinase phosphorylates the GS domain of the type I receptor, a critical event in signal transduction by the serine/threonine kinase receptors (Miyazono et al. 2010). Activation of the TGFBR1 receptor has been studied in detail. The inactive conformation is maintained by interaction between the GS domain, the N-terminal lobe and the activation loop of the kinase (Huse et al. 1999). When the GS domain is phosphorylated by the type II receptor kinase, the TGFBR1 kinase is converted to an active conformation. Mutations of Thr-204 in TGFBR1 and the corresponding Gln in BMP type I receptors lead to their constitutive activation. The L45 loop, in the kinase domain of type I receptors, specifically interacts with receptor-regulated Smads (R-Smads). Neurotrophic tyrosine kinase receptor type 3 (NT-3 growth factor receptor, TrkC, NTRK3) directly binds BMPR2, interfereing with its interaction with BMPR1A, which inhibits downstream signalling (Jin et al. 2007). Tyrosine-protein kinase transmembrane receptor ROR2 and BMPR1B form a heteromeric complex in a ligand independent fashion that modulatesGDF5-BMPR1B signalling by inhibition of Smad1/5 signalling (Sammar et al. 2004). Type I receptor kinases activated by the type II receptor kinases, phosphorylate R-Smads. R-Smads then form a complex with common-partner Smad (co-Smad) and translocate to the nucleus. The oligomeric Smad complexes regulate the transcription of target genes through interaction with various transcription factors and transcriptional coactivators or corepressors. Inhibitory Smads (I-Smads) negatively regulate the action of R-Smads and/or co-Smads. Eight different Smads have been identified in mammals. Smad1, Smad5 and Smad8 are R-Smads in BMP signalling pathways (BMP-specific R-Smads). Smad2 and Smad3 are R-Smads in TGFB/activin
signalling pathways. BMP receptors can phosphorylate Smad2 in certain types of cells (Murakami et al. 2009). Smad1, Smad5 and Smad8 are structurally highly similar to each other. The functional differences between them are largely unknown. Smad4 is the only co-Smad in mammals, shared by both BMP and TGFB/activin signalling pathways. Smad6 and Smad7 are I-Smads.
Signaling by NOTCH1PathwayR-HSA-1980143 (Reactome) NOTCH1 functions as both a transmembrane receptor presented on the cell surface and as a transcriptional regulator in the nucleus.

NOTCH1 receptor presented on the plasma membrane is activated by a membrane bound ligand expressed in trans on the surface of a neighboring cell. In trans, ligand binding triggers proteolytic cleavage of NOTCH1 and results in release of the NOTCH1 intracellular domain, NICD1, into the cytosol.

NICD1 translocates to the nucleus where it associates with RBPJ (also known as CSL or CBF) and mastermind-like (MAML) proteins (MAML1, MAML2 or MAML3; possibly also MAMLD1) to form NOTCH1 coactivator complex. NOTCH1 coactivator complex activates transcription of genes that possess RBPJ binding sites in their promoters.

TEST MetaboliteCHEBI:17347 (ChEBI)
TWIST1 ProteinQ15672 (Uniprot-TrEMBL)
TWIST1,TWIST2ComplexR-HSA-9007859 (Reactome)
TWIST2 ProteinQ8WVJ9 (Uniprot-TrEMBL)
Transcriptional regulation by RUNX1PathwayR-HSA-8878171 (Reactome) The RUNX1 (AML1) transcription factor is a master regulator of hematopoiesis (Ichikawa et al. 2004) that is frequently translocated in acute myeloid leukemia (AML), resulting in formation of fusion proteins with altered transactivation profiles (Lam and Zhang 2012, Ichikawa et al. 2013). In addition to RUNX1, its heterodimerization partner CBFB is also frequently mutated in AML (Shigesada et al. 2004, Mangan and Speck 2011).
The core domain of CBFB binds to the Runt domain of RUNX1, resulting in formation of the RUNX1:CBFB heterodimer. CBFB does not interact with DNA directly. The Runt domain of RUNX1 mediated both DNA binding and heterodimerization with CBFB (Tahirov et al. 2001), while RUNX1 regions that flank the Runt domain are involved in transactivation (reviewed in Zhang et al. 2003) and negative regulation (autoinhibition). CBFB facilitates RUNX1 binding to DNA by stabilizing Runt domain regions that interact with the major and minor grooves of the DNA (Tahirov et al. 2001, Backstrom et al. 2002, Bartfeld et al. 2002). The transactivation domain of RUNX1 is located C-terminally to the Runt domain and is followed by the negative regulatory domain. Autoinhibiton of RUNX1 is relieved by interaction with CBFB (Kanno et al. 1998).
Transcriptional targets of the RUNX1:CBFB complex involve genes that regulate self-renewal of hematopoietic stem cells (HSCs) (Zhao et al. 2014), as well as commitment and differentiation of many hematopoietic progenitors, including myeloid (Friedman 2009) and megakaryocytic progenitors (Goldfarb 2009), regulatory T lymphocytes (Wong et al. 2011) and B lymphocytes (Boller and Grosschedl 2014).
RUNX1 binds to promoters of many genes involved in ribosomal biogenesis (Ribi) and is thought to stimulate their transcription. RUNX1 loss-of-function decreases ribosome biogenesis and translation in hematopoietic stem and progenitor cells (HSPCs). RUNX1 loss-of-function is therefore associated with a slow growth, but at the same time it results in reduced apoptosis and increases resistance of cells to genotoxic and endoplasmic reticulum stress, conferring an overall selective advantage to RUNX1 deficient HSPCs (Cai et al. 2015).
RUNX1 is implicated as a tumor suppressor in breast cancer. RUNX1 forms a complex with the activated estrogen receptor alpha (ESR1) and regulates expression of estrogen-responsive genes (Chimge and Frenkel 2013).
RUNX1 is overexpressed in epithelial ovarian carcinoma where it may contribute to cell proliferation, migration and invasion (Keita et al. 2013).
RUNX1 may cooperate with TP53 in transcriptional activation of TP53 target genes upon DNA damage (Wu et al. 2013).
RUNX1 is needed for the maintenance of skeletal musculature (Wang et al. 2005).
During mouse embryonic development, Runx1 is expressed in most nociceptive sensory neurons, which are involved in the perception of pain. In adult mice, Runx1 is expressed only in nociceptive sensory neurons that express the Ret receptor and is involved in regulation of expression of genes encoding ion channels (sodium-gated, ATP-gated and hydrogen ion-gated) and receptors (thermal receptors, opioid receptor MOR and the Mrgpr class of G protein coupled receptors). Mice lacking Runx1 show defective perception of thermal and neuropathic pain (Chen CL et al. 2006). Runx1 is thought to activate the neuronal differentiation of nociceptive dorsal root ganglion cells during embryonal development possibly through repression of Hes1 expression (Kobayashi et al. 2012). In chick and mouse embryos, Runx1 expression is restricted to the dorso-medial domain of the dorsal root ganglion, to TrkA-positive cutaneous sensory neurons. Runx3 expression in chick and mouse embryos is restricted to ventro-lateral domain of the dorsal root ganglion, to TrkC-positive proprioceptive neurons (Chen AI et al. 2006, Kramer et al. 2006). RUNX1 mediated regulation of neuronally expressed genes will be annotated when mechanistic details become available.
UCMA gene ProteinENSG00000165623 (Ensembl)
UCMA geneGeneProductENSG00000165623 (Ensembl)
UCMAProteinQ8WVF2 (Uniprot-TrEMBL)
WWTR1 ProteinQ9GZV5 (Uniprot-TrEMBL)
WWTR1ProteinQ9GZV5 (Uniprot-TrEMBL)
YAP1 ProteinP46937 (Uniprot-TrEMBL)
YAP1ProteinP46937 (Uniprot-TrEMBL)
ZNF521 ProteinQ96K83 (Uniprot-TrEMBL)
ZNF521ProteinQ96K83 (Uniprot-TrEMBL)
androst-4-en-3,17-dione MetaboliteCHEBI:16422 (ChEBI)
p-2S-RUNX2:CBFBComplexR-HSA-9009233 (Reactome)
p-2S-SMAD1:p-2S-SMAD1:SMAD4ComplexR-HSA-206654 (Reactome)
p-S183,T185,T187-RUNX2-P2 ProteinQ13950-2 (Uniprot-TrEMBL)
p-S196,T198,T200-RUNX2-P1 ProteinQ13950-1 (Uniprot-TrEMBL)
p-S196,T198,T200-RUNX2:CBFB:MMP13 geneComplexR-HSA-8939999 (Reactome)
p-S196,T198,T200-RUNX2:CBFBComplexR-HSA-8939962 (Reactome)
p-S280,S298-RUNX2-P2 ProteinQ13950-2 (Uniprot-TrEMBL)
p-S294,S312-RUNX2-P1 ProteinQ13950-1 (Uniprot-TrEMBL)
p-S418-RUNX2-P2 ProteinQ13950-2 (Uniprot-TrEMBL)
p-S432-RUNX2-P1 ProteinQ13950-1 (Uniprot-TrEMBL)
p-S432-RUNX2:CBFBComplexR-HSA-9008869 (Reactome)
p-S451-RUNX2-P2 ProteinQ13950-2 (Uniprot-TrEMBL)
p-S451-RUNX2:CBFBComplexR-HSA-9008410 (Reactome)
p-S463,S465-SMAD1 ProteinQ15797 (Uniprot-TrEMBL)
p-S465-RUNX2-P1 ProteinQ13950-1 (Uniprot-TrEMBL)
p-T,Y MAPK dimersComplexR-HSA-198701 (Reactome)
p-T,p-S-AKTComplexR-HSA-202072 (Reactome)
p-T161-CDK1 ProteinP06493 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-Y-YAP1 ProteinP46937 (Uniprot-TrEMBL)
p-Y-YAP1ProteinP46937 (Uniprot-TrEMBL)
p-Y226,Y393-ABL1ProteinP00519 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(p-S451-RUNX2:CBFB,RUNX2:CBFB,RUNX2:HDAC6):CDKN1A geneArrowR-HSA-9008433 (Reactome)
(p-S451-RUNX2:CBFB,RUNX2:CBFB,RUNX2:HDAC6):CDKN1A geneTBarR-HSA-9008456 (Reactome)
(p-S451-RUNX2:CBFB,RUNX2:CBFB,RUNX2:HDAC6)R-HSA-9008433 (Reactome)
2p-GLI2R-HSA-8986294 (Reactome)
ADPArrowR-HSA-8937844 (Reactome)
ADPArrowR-HSA-8939963 (Reactome)
ADPArrowR-HSA-9008412 (Reactome)
ADPArrowR-HSA-9009208 (Reactome)
ADPArrowR-HSA-9009282 (Reactome)
AR:androgenR-HSA-8877902 (Reactome)
ATPR-HSA-8937844 (Reactome)
ATPR-HSA-8939963 (Reactome)
ATPR-HSA-9008412 (Reactome)
ATPR-HSA-9009208 (Reactome)
ATPR-HSA-9009282 (Reactome)
BAX geneR-HSA-9008832 (Reactome)
BAX geneR-HSA-9008839 (Reactome)
BAXArrowR-HSA-9008839 (Reactome)
BGLAP geneR-HSA-8877918 (Reactome)
BGLAP geneR-HSA-8877922 (Reactome)
BGLAP geneR-HSA-8937869 (Reactome)
BGLAP geneR-HSA-8985227 (Reactome)
BGLAP geneR-HSA-8985485 (Reactome)
BGLAP geneR-HSA-9008877 (Reactome)
BGLAP(24-100)ArrowR-HSA-8877922 (Reactome)
BMP2 dimerArrowR-HSA-9008832 (Reactome)
CBFBR-HSA-8865425 (Reactome)
CCNB1:p-T161-CDK1mim-catalysisR-HSA-9009282 (Reactome)
CCND1:CDK4mim-catalysisR-HSA-9008412 (Reactome)
CDKN1A geneR-HSA-9008433 (Reactome)
CDKN1A geneR-HSA-9008456 (Reactome)
CDKN1AArrowR-HSA-9008456 (Reactome)
COL1A1 geneR-HSA-8985627 (Reactome)
COL1A1 geneR-HSA-8985644 (Reactome)
COL1A1ArrowR-HSA-8985644 (Reactome)
GLI3RR-HSA-9008215 (Reactome)
H2OR-HSA-9008822 (Reactome)
HAND2R-HSA-9007816 (Reactome)
HDAC3R-HSA-9008137 (Reactome)
HDAC4R-HSA-9008326 (Reactome)
HDAC6R-HSA-9008389 (Reactome)
HEY1,HEY2,HES1R-HSA-9008177 (Reactome)
IHH geneR-HSA-8878257 (Reactome)
IHH geneR-HSA-8878266 (Reactome)
IHHArrowR-HSA-8878266 (Reactome)
ITGA5 geneR-HSA-8939667 (Reactome)
ITGA5 geneR-HSA-8939670 (Reactome)
ITGA5(42-894)ArrowR-HSA-8939667 (Reactome)
ITGBL1 geneR-HSA-8939829 (Reactome)
ITGBL1 geneR-HSA-8939833 (Reactome)
ITGBL1ArrowR-HSA-8939829 (Reactome)
LGALS3 geneR-HSA-8938371 (Reactome)
LGALS3 geneR-HSA-8938382 (Reactome)
LGALS3ArrowR-HSA-8938382 (Reactome)
MAFR-HSA-8984994 (Reactome)
MMP13 geneR-HSA-8940001 (Reactome)
MMP13 geneR-HSA-8940007 (Reactome)
MMP13ArrowR-HSA-8940007 (Reactome)
MyrG-p-Y419-SRC,MyrG-p-Y426-YES1:YAP1ArrowR-HSA-8937820 (Reactome)
MyrG-p-Y419-SRC,MyrG-p-Y426-YES1:YAP1R-HSA-8937844 (Reactome)
MyrG-p-Y419-SRC,MyrG-p-Y426-YES1:YAP1mim-catalysisR-HSA-8937844 (Reactome)
MyrG-p-Y419-SRC,MyrG-p-Y426-YES1ArrowR-HSA-8937844 (Reactome)
MyrG-p-Y419-SRC,MyrG-p-Y426-YES1R-HSA-8937820 (Reactome)
PPM1Dmim-catalysisR-HSA-9008822 (Reactome)
PPiArrowR-HSA-9008822 (Reactome)
R-HSA-2064932 (Reactome) In the nucleus the WWTR1 (TAZ) transcriptional coactivator can bind the RUNX2 transcription factor to form a complex. This interaction has not been experimentally characterized in human cells but is inferred from properties of the homologous mouse proteins. The stoichiometry of this complex is unknown (Cui et al. 2003).

Formation of the RUNX2:WWTR1 complex is implicated in promotion of luminal breast cancer progression through regulation of E-cadherin (CDH1) and cross-talk with ERBB2 (HER2) signaling (Brusgard et al. 2015).

R-HSA-8865425 (Reactome) RUNX2 (CBFA1 or AML3) forms a complex with CBFB. RUNX2 gene mutations are the cause of cleidocranial dysplasia and some of the mutations are predicted to affect RUNX2 interaction with CBFB (Otto et al. 1997, Lee et al. 1997, Otto et al. 2002). In mouse cleidocranial dysplasia models, the physical and functional interaction between Runx2 and Cbfb was demonstrated to play a critical role in bone development (Kundu et al. 2002, Yoshida et al. 2002, Chen et al. 2014).
R-HSA-8877902 (Reactome) Androgen receptor (AR), activated by binding to androgens, forms a complex with RUNX2 (presumably associated with CBFB) in the nucleus. AR inhibits transcriptional activity of RUNX2, which may underlie AR-mediated attenuation of bone turnover. RUNX2 may play a tumor suppressor role in prostate cancer (Baniwal et al. 2009).

The complex of RUNX2 and AR is implicated in stimulation of the PSA gene transcription in response to TGF-beta signaling, but further experimental validation is needed (van der Deen et al. 2010).

R-HSA-8877918 (Reactome) RUNX2 binds the OSE2 element in the promoter of the BGLAP (osteocalcin, OC) gene. Formation of the complex between the activated androgen receptor (AR) and RUNX2 prevents RUNX2 from binding the BGLAP gene promoter (Baniwal et al. 2009). Based on studies in mice, RUNX2 binds to the BGLAP promoter in complex with the MAF transcription factor, and RUNX2 and MAF act synergistically to induce BGLAP transcription (Nishikawa et al. 2010). RUNX2 binding sites are conserved in the human BGLAP gene promoter.
R-HSA-8877922 (Reactome) Binding of RUNX2 to the OSE2 element in the promoter of the BGLAP (osteocalcin, OC) gene stimulates BGLAP transcription (Ducy and Karsenty 1995, Ducy et al. 1997). When RUNX2 binds the OSE2 element in complex with the MAF transcription factor, BGLAP transcription is enhanced (Nishikawa et al. 2010). BGLAP gene transcription is also directly stimulated by the complex of RUNX2 and WWTR1 (TAZ) (Hong et al. 2005), as well as the complex of RUNX2 and RB1 (Thomas et al. 2001). Phosphorylation of RUNX2, in the context of the RUNX2:CBFB complex, increases its association with the BGLAP promoter and enhances BGLAP transcription (Wee et al. 2002, Ge et al. 2009). Osteocalcin, a bone-derived hormone, is one of the most abundant non-collagenous proteins of the bone extracellular matrix (reviewed in Karsenty and Olson 2016).
Association of the activated androgen receptor (AR) with RUNX2 prevents binding of RUNX2 to the BGLAP promoter (Baniwal et al. 2009). Based on studies in rat, when YAP1, phosphorylated on an unknown tyrosine residue by SRC and/or YES1, is present in the complex with RUNX2 at the BGLAP gene promoter, transcription of the BGLAP gene is inhibited (Zaidi et al. 2004). Signaling by SRC is known to inhibit osteoblast differentiation (Marzia et al. 2000). Based on studies in mice, binding to ZNF521 (ZNP521) inhibits RUNX2-mediated activation of target promoters, such as BGLAP. HDAC3 is needed for ZNF521 to inhibit RUNX2-mediated transcription from the BGLAP promoter. Action of ZNF521 antagonizes RUNX2 during mesenchymal commitment to the osteoblast lineage and during osteoblast maturation (Hesse et al. 2010).
R-HSA-8877941 (Reactome) In response to BMP2 treatment, RUNX2 (presumably associated with CBFB) forms a complex with SMAD1 (Wang et al. 2006). Phosphorylation of SMAD1 in response to BMP signaling and formation of a heterotrimeric complex between phosphorylated SMAD1 and SMAD4 are prerequisites for SMAD1 retention in the nucleus (Qin et al. 2001, Xiao et al. 2001).

BMP2 signaling is implicated in promoting formation of a complex between RUNX2, SMAD1 and acetyltransferase EP300 (p300) and facilitating EP300-mediated acetylation of RUNX2, which activates RUNX2 transcriptional activity. This may involve ERK-mediated phosphorylation of RUNX2 and/or EP300 downstream of BMP2, but the exact mechanism has not been elucidated (Jun et al. 2010).

R-HSA-8878013 (Reactome) The complex containing RUNX2 and SMAD1 activated downstream of BMP2 signaling, binds the promoter of the SMAD6 gene (Wang et al. 2007).
R-HSA-8878023 (Reactome) Binding of the complex of RUNX2 and SMAD1 to the promoter of the SMAD6 gene positively regulates SMAD6 transcription (Wang et al. 2007).
R-HSA-8878257 (Reactome) Based on studies in mice, RUNX2, presumably associated with CBFB, binds the evolutionarily conserved RUNX2 response elements in the promoter of the IHH (Indian hedgehog) gene (Yoshida et al. 2004).
R-HSA-8878266 (Reactome) Based on studies in mice, binding of RUNX2, presumably in complex with CBFB, to evolutionarily conserved RUNX2 response elements in the promoter of the IHH gene stimulates IHH transcription. The IHH gene encodes Indian hedgehog, which controls limb growth by regulating chondrocyte proliferation and maturation (Yoshida et al. 2004).
R-HSA-8937820 (Reactome) Based on studies in rat osteosarcoma cell line, activated SRC and YES1 form a complex with YAP1 (Zaidi et al. 2004).
R-HSA-8937844 (Reactome) Based on studies in rat, activated SRC and/or YES1 tyrosine kinases phosphorylate YAP1 on an unknown tyrosine residue (Zaidi et al. 2004).
R-HSA-8937856 (Reactome) Based on studies in rat, YAP1, phosphorylated on an unknown tyrosine residue by SRC and/or YES1, translocates to the nucleus. Tyrosine phosphorylated YAP1 shuffles between the nucleus and the cytosol, and phosphorylation by SRC and/or YES1 does not change the ratio of nuclear and cytosolic YAP1 (Zaidi et al. 2004).
R-HSA-8937864 (Reactome) Based on studies in rat, RUNX2, presumably associated with CBFB, binds YAP1, phosphorylated on an unknown tyrosine residue by SRC and/or YES1. The interaction involves the PY motif of RUNX2 (Zaidi et al. 2004).
R-HSA-8937869 (Reactome) Based on studies in rat, the complex of RUNX2, presumably associated with CBFB, and tyrosine phosphorylated YAP1 binds to the promoter of the BGLAP (osteocalcin) gene (Zaidi et al. 2004). RUNX2 binding sites are conserved in the human BGLAP gene promoter.
R-HSA-8938356 (Reactome) RBM14 (CoAA) binds RUNX2. This interaction involves the C-terminus of RBM14 and the Runt domain of RUNX2. It has not been examined whether RBM14 interacts with RUNX2 alone or in the context of the RUNX2:CBFB complex. Formation of the RUNX2:RBM14 complex prevents binding of RUNX2 to its target promoters and thus interferes with activation of RUNX2 target genes. RBM14 is frequently overexpressed in osteosarcoma (Li et al. 2009).
R-HSA-8938371 (Reactome) The RUNX2:CBFB complex binds the RUNX2 response element in the promoter of the LGLAS3 gene, encoding Galectin-3 (Vladimirova et al. 2008, Zhang et al. 2009).
R-HSA-8938382 (Reactome) Binding of the RUNX1:CBFB or RUNX2:CBFB complex to RUNX response elements in the promoter of the LGALS3 gene stimulates LGLAS3 transcription. The LGALS3 gene encodes Galectin-3, which is highly expressed in pituitary tumors and glioma (Vladimirova et al. 2008, Zhang et al. 2009). Galectin-3 is expressed in myeloid progenitors and its levels increase during the maturation process (Le Marer 2000).
R-HSA-8939667 (Reactome) Binding of RUNX2, presumably associated with CBFB, to OSE2 (osteoblast specific element 2) sites in the promoter of the ITGA5 stimulates ITGA5 transcription. Integrin alpha-5, encoded by the ITGA5 gene, promotes adhesion of breast cancer cells to the bone, thus facilitating formation of bone metastases (Li et al. 2016).
R-HSA-8939670 (Reactome) RUNX2, presumably associated with CBFB, binds to OSE2 (osteoblast-specific cis-acting element 2) sites in the promoter of the ITGA5 gene, encoding Integrin alpha-5 (Li et al. 2016).
R-HSA-8939829 (Reactome) Binding of RUNX2, presumably associated with CBFB, to RUNX2 response elements in the promoter of the ITGBL1 gene stimulates ITGBL1 transcription. ITGBL1 encodes Integrin beta-like protein 1, which is implicated in regulation of TGF-beta signaling and RUNX2-induced bone metastasis of breast cancer (Li et al. 2015).
R-HSA-8939833 (Reactome) RUNX2, presumably associated with CBFB, binds to RUNX2 binding sites in the promoter of the ITGBL1 gene, encoding Integrin beta-like protein 1 (Li et al. 2015).
R-HSA-8939852 (Reactome) Based on mouse studies, RUNX2, presumably associated with CBFB, and SP7 (also known as Osterix or OSX), bind to adjacent RUNX2 and OSX binding sites, respectively, in the promoter of the UCMA gene. RUNX2 and OSX binding sites in the UCMA promoter are evolutionarily conserved. It is not clear whether RUNX2 and SP7 directly physically interact (Lee et al. 2015).
R-HSA-8939870 (Reactome) While RUNX2 and SP7 (OSX), based on mouse studies, can stimulate the UCMA gene expression independently of each other, simultaneous binding of RUNX2 and SP7 to adjacent RUNX2 and SP7 binding sites, respectively, in the UCMA promoter, synergistically activates UCMA transcription. UCMA stimulates osteoblast differentiation and formation of mineralized nodules (Lee et al. 2015).
R-HSA-8939963 (Reactome) Activated AKT phosphorylates RUNX2 without affecting its association with CBFB or its nuclear localization. Based on studies using recombinant mouse Runx2, the most prominent AKT target sites in human RUNX2 are inferred to be serine residue S196 and threonine residues T198 and T200. These sites are evolutionarily conserved and match S203, T205 and T207 of the recombinant mouse Runx2 (Pande et al. 2013). In addition to phosphorylating RUNX2, which increases its affinity for some target promoters (Pande et al. 2013), AKT signaling also stabilizes RUNX2 protein. Increased AKT signaling, achieved by knocking down PTEN, a negative regulator of AKT activation, reduces RUNX2 protein degradation, which possibly involves AKT-mediated nuclear exclusion of transcription factors FOXO1 and FOXO3. Increased RUNX2 activity in response to AKT signaling is implicated in vascular calcification, a pathological feature of atherosclerosis, diabetes mellitus and renal disease (Deng et al. 2015).
R-HSA-8940001 (Reactome) AKT-mediated phosphorylation of RUNX2 increases affinity of the RUNX2:CBFB complex for the promoter of the MMP13 gene, encoding Colagenase-3 (Matrix metalloproteinase-13) (Pande et al. 2013).
R-HSA-8940007 (Reactome) RUNX2:CBFB-mediated transcription of the MMP13 gene, encoding Colagenase-3 (Matrix metalloproteinase-13), is stimulated by AKT-mediated phosphorylation of RUNX2 and is implicated in invasiveness of breast cancer cells (Pande et al. 2013).
R-HSA-8984994 (Reactome) Based on studies in mice, RUNX2 forms a complex with the transcription factor MAF. It is unknown whether MAF participates in this complex as a homodimer or a monomer. It is also unknown whether RUNX2 is bound to CBFB when in complex with MAF (Nishikawa et al. 2010).
R-HSA-8985227 (Reactome) Based on studies in mouse cells, the complex of RUNX2 and WWTR1 (TAZ) binds to the promoter of the BGLAP gene, encoding osteocalcin (Hong et al. 2005). Catalytically active protein tyrosine kinase ABL1 promotes association of RUNX2 and WWTR1 and transcription of the BGLAP gene (Matsumoto et al. 2016). RUNX2 binding sites are conserved in the human BGLAP gene promoter.
R-HSA-8985275 (Reactome) Based on studies in mice, RUNX2 forms a complex with the transcription factor SATB2. SATB2 may promote transcription of RUNX2 targets, including osteocalcin (BGLAP) (Dobreva et al. 2006).
R-HSA-8985343 (Reactome) SOX9 binds to RUNX2 and represses its transcriptional activity (Zhou et al. 2006).
R-HSA-8985460 (Reactome) RUNX2 forms a complex with the tumor suppressor RB1. The C-terminus and B-pocket of RB1 are needed for the interaction (Thomas et al. 2001).
R-HSA-8985485 (Reactome) The complex of RUNX2 and RB1 binds the promoter of the BGLAP gene, encoding osteocalcin (Thomas et al. 2001, Calo et al. 2010).
R-HSA-8985627 (Reactome) Based on studies in mice, the complex of RUNX2 and RB1 binds to RUNX2-binding elements in the promoter of the COL1A1 gene encoding Collagen alpha-1(I) chain (Kern et al. 2001, Calo et al. 2010). RUNX2 binding sites are conserved in the human COL1A1 gene promoter.
R-HSA-8985644 (Reactome) Based on mouse studies, binding of the RUNX2:RB1 complex to RUNX2-response elements in the promoter of the COL1A1 gene, encoding Collagen alpha-1(I) chain, stimulates COL1A1 transcription (Kern et al. 2001, Cola et al. 2010).
R-HSA-8986294 (Reactome) GLI2, activated in response to Indian Hedgehog (IHH) signaling, forms a complex with RUNX2 and enhances transcriptional activity of RUNX2 (Shimoyama et al. 2007).
R-HSA-9007816 (Reactome) Based on studies in mice, RUNX2 binds to the basic helix-loop-helix (bHLH) protein HAND2. The interaction involves the N-terminal part of HAND2 and the Runt DNA binding domain of RUNX2. Interaction with HAND2 prevents binding of RUNX2 to the DNA, thus inhibiting transcriptional activation of RUNX2 target genes. HAND1 is also able to bind to RUNX2 and inhibit binding of RUNX2 to the DNA, but this interaction is not considered to be physiologically relevant as RUNX2 and HAND1 are not coexpressed in vivo, and targeted deletion of Hand1 in mice does not lead to skeletal defects. Mice hypomorphic for a mutant Hand2 allele, however, show abnormal membranous bone phenotype, accompanied with elevated Runx2 expression and precocious and accelerated osteoblast differentiation (Funato et al. 2009).

In mouse tissues, Hand2 expression is also associated with Runx2 downregulation (Funato et al. 2009, Barron et al. 2011). This could be due to the suggested Hand2-mediated transcriptional repression of Dlx5 and Dlx6, two transcription factors involved in stimulation of Runx2 expression (Barron et al. 2011).

R-HSA-9007860 (Reactome) Based on studies in mice, TWIST1 and TWIST2 can bind, via their TWIST domain, to the Runt DNA binding domain of RUNX2. Binding to TWIST1 or TWIST2 inhibits transactivation activity of RUNX2 and delays the onset of osteoblast differentiation (Bialek et al. 2004). In addition, binding of RUNX2 to TWIST1 inhibits TWIST1-mediated induction of FGFR2 transcription (Lu et al. 2012). The interplay of RUNX2 and TWIST1 is implicated in the differentiation of odontoblasts (Li et al. 2011).
R-HSA-9008137 (Reactome) Based on studies in mice, RUNX2 forms a complex with ZNF521 (ZNP521) and a histone deacetylase HDAC3. Binding to ZNF521 does not inhibit RUNX2 binding to target genes, such as the BGLAP (Osteocalcin) gene promoter, but inhibits RUNX2-mediated activation of these genes. HDAC3 is needed for ZNF521 to inhibit RUNX2-mediated transcription from the BGLAP promoter. Action of ZNF521 antagonizes RUNX2 during mesenchymal commitment to the osteoblast lineage and during osteoblast maturation (Hesse et al. 2010).
R-HSA-9008177 (Reactome) Based on studies in mice, RUNX2 forms a complex with HEY2 (HRT2), a product of the NOTCH1 target gene. Binding to HEY2 inhibits RUNX2-mediated transcriptional activation of the BGLAP (Osteocalcin) gene (Garg et al. 2005). Other NOTCH1 targets, HEY1 and HES1, can also bind to RUNX2 and inhibit RUNX2 transcriptional activity (Hilton et al. 2008). NOTCH1 mutations cause severe aortic valve calcification in humans, which may be due to impaired repression of RUNX2-mediated transcription (Garg et al. 2005). NOTCH-mediated inhibition of RUNX2 transcriptional activity is also implicated in the maintenance of mesenchymal progenitors in the bone marrow by suppression of osteoblast differentiation (Hilton et al. 2008).

NOTCH1 may also inhibit RUNX2-mediated activation of target promoters by formation of a complex between RUNX2 and NOTCH1 intracellular domain (NICD1) (Engin et al. 2008).

R-HSA-9008215 (Reactome) Based on studies in mice, GLI3R, a repressive form of GLI3 generated in the Hedgehog "off" state, binds to RUNX2 and inhibits binding of RUNX2 to DNA. Cells haploinsufficient for PTCH1 generate less GLI3R, which is associated with increased RUNX2 activity and accelerated osteoblast differentiation (Ohba et al. 2008).
R-HSA-9008326 (Reactome) Based on studies in mice, RUNX2 forms a complex with the histone deacetylase HDAC4. The interaction involves the Runt DNA binding domain of RUNX2 and leads to inhibition of RUNX2 binding to its target DNA sequences. Specifically, interference with RUNX2 binding to the RUNX2 promoter in the presence of HDAC4 has been demonstrated. Hdac4 knockout mice develop premature ossification of developing bones because of premature and ectopic onset of chondrocyte hypertrophy. This phenotype is similar to the Runx2 overexpression phenotype in mouse chondrocytes (Vega et al. 2004).
R-HSA-9008389 (Reactome) Based on studies in rat osteoblast, RUNX2 forms a complex with the histone deacetylase HDAC6 (Westendorf et al. 2002).
R-HSA-9008412 (Reactome) In endothelial cells, in response to high glucose, probably via glucose-mediated upregulation of CCND1 (cyclin D1) transcription, activated CDK4 phosphorylates RUNX2 on serine residue S451 (S451 in RUNX2-P2 isoform transcribed from the proximal P2 promoter matches S465 in RUNX2-P1 isoform transcribed from the distal P1 promoter). CDK4-mediated phosphorylation is assumed to happen in the context of the RUNX2:CBFB complex, as phosphorylation at S451 does not affect RUNX2 binding to CBFB (Wee et al. 2002). RUNX2 phosphorylated at S451 shows increased binding to target promoters, CDKN1A (p21) in particular, which enhances RUNX2-mediated repression of CDKN1A transcription (Pierce et al. 2012). Phosphorylation of RUNX2 at S451 also enhances binding of the RUNX2:CBFB complex to the osteocalcin gene promoter (Wee et al. 2002).

Phosphorylation of RUNX2-P1 serine site S465 (corresponds to mouse Runx2-P1 serine residue S472) by the CDK4:CCND1 complex has been reported to target RUNX2 for ubiquitination and proteasome-mediated degradation, but the responsible ubiquitin ligase has not been identified (Shen et al. 2006). BMP2 signaling was reported to interfere with CDK4-induced RUNX2 protein degradation (Shu et al. 2011). Parathyroid hormone-related protein (PTHLH, also known as PTHrP) is implicated in positive regulation of CCND1-mediated degradation of RUNX2 (Zhang et al. 2009).

R-HSA-9008433 (Reactome) RUNX2, presumably in complex with at least CBFB, binds to at least two of the three RUNX2-binding sites in the promoter of the CDKN1A (p21) gene. CDK4-mediated phosphorylation of RUNX2 enhances binding of RUNX2 to the CDKN1A promoter (Pierce et al. 2012). The complex of RUNX2 and HDAC6 is also implicated in regulation of the CDKN1A promoter (Westendorf et al. 2002).
R-HSA-9008456 (Reactome) Binding of RUNX2 to the CDKN1A gene promoter inhibits CDKN1A transcription, thus preventing CDKN1A-induced cell cycle arrest. Phosphorylation of RUNX2 by CDK4 in response to high glucose enhances RUNX2-mediated repression of the CDKN1A gene in endothelial cells (Pierce et al. 2012). HDAC6, which forms a complex with RUNX2, may contribute to RUNX2-mediated repression of CDKN1A in developing osteoblasts (Westendorf et al. 2002). In mice, Runx2-mediated repression of Cdkn1a may contribute to the development of acute myeloid leukemia (AML) (Kuo et al. 2009).
R-HSA-9008822 (Reactome) PPM1D (Wip1), a serine/threonine phosphatase, dephosphorylates RUNX2 on serine residue S432. Since it has not been tested whether S432 affects bindng of RUNX2 to CBFB, PPM1D is shown to dephosphorylate RUNX2 in the context of its complex with CBFB. The kinase responsible for RUNX2 phosphorylation at S432 is not known. PPM1D-mediated dephosphorylation of RUNX2 promotes RUNX2-mediated transcriptional activation of BAX and may play an important role in inducing apoptosis in TP53 negative tumor cells (Goloudina, Tanoue et al. 2012, Goloudina, Mazur et al. 2012).
R-HSA-9008832 (Reactome) RUNX2, presumably in complex with CBFB, binds the promoter of the BAX gene (Eliseev et al. 2008, Goloudina, Tanoue et al. 2012, Goloudina, Mazur et al. 2012). Signaling downstream of BMP2 promotes RUNX2-mediated activation of the BAX gene transcription (Eliseev et al. 2008). Dephosphorylation of RUNX2 serine residue S432 by the PPM1D (WIP1) serine/threonine phosphatase promotes association of RUNX2 with the BAX promoter (Goloudina, Tanoue et al. 2012, Goloudina, Mazur et al. 2012).
R-HSA-9008839 (Reactome) BAX gene transcription is directly stimulated by binding of RUNX2, presumably in complex with CBFB, to RUNX2 response elements in the BAX promoter (Eliseev et al. 2008, Goloudina, Tanoue et al. 2012, Goloudina, Mazur et al. 2012).
R-HSA-9008877 (Reactome) RUNX2 binds the OSE2 element in the promoter of the BGLAP (osteocalcin, OC) gene (Ducy and Karsenty 1995, Ducy et al. 1997). The affinity of the RUNX2:CBFB complex for the BGLAP gene promoter is increased when RUNX2 is phosphorylated on serine residue S451 (Wee et al. 2002), or on serine residues S294 and S312, which correspond to mouse Runx2-P1 residues S472, S301 and S319 (Ge et al. 2009). Formation of the complex between the activated androgen receptor (AR) and RUNX2 prevents RUNX2 from binding the BGLAP promoter (Baniwal et al. 2009). Twist proteins and Schnurri-3 also interact with RUNX2 to decrease BGLAP expression (Bialek et al. 2004, Jones et al. 2006). In contrast, RUNX2 and SATB2 interact to enhance the expression of osteoblast-specific genes (Dobreva et al. 2006).
R-HSA-9009208 (Reactome) RUNX2 is phosphorylated by activated ERKs (MAPK3 and MAPK1) on at least two conserved serine residues. ERK-mediated phosphorylation is not known to affect binding of RUNX2 to CBFB and is therefore shown to happen in the context of the RUNX2:CBFB complex. RUNX2 phosphorylated by ERKs shows enhanced binding to RUNX2 response elements in the osteocalcin (BGLAP) gene promoter, resulting in increased BGLAP gene transcription (Ge et al. 2009).

ERK-mediated phosphorylation of RUNX2 in response to FGF2 signaling is thought to promote RUNX2 isomerization by PIN1 prolyl isomerase, which facilitates EP300 (p300) mediated acetylation and stabilization of RUNX2 (Yoon et al. 2014).

R-HSA-9009282 (Reactome) RUNX2, presumably in complex with CBFB, can be phosphorylated by the complex of CDK1 and cyclin B. The interaction was demonstrated between endogenous human RUNX2 and CDK1:CCNB1. It was also shown in human cells that RUNX2 undergoes CDK1:CCNB1-mediated phosphorylation on serine residue S451 of RUNX2-P2 isoform. This residue corresponds to the mouse Runx-P1 serine residue S472 (Qiao et al. 2006, Rajgopal et al. 2007). At mitotic exit, RUNX2 is dephosphorylated by unidentified PP1 or PP2A phosphatase (Rajgopal et al. 2007).
RB1R-HSA-8985460 (Reactome)
RBM14R-HSA-8938356 (Reactome)
RUNX1:CBFB:LGALS3 geneArrowR-HSA-8938382 (Reactome)
RUNX2:2p-GLI2ArrowR-HSA-8986294 (Reactome)
RUNX2:AR:androgenArrowR-HSA-8877902 (Reactome)
RUNX2:AR:androgenTBarR-HSA-8877918 (Reactome)
RUNX2:CBFB,p-S451-RUNX2:CBFB,(p-2S-RUNX2:CBFB):BGLAP geneArrowR-HSA-8877922 (Reactome)
RUNX2:CBFB,p-S451-RUNX2:CBFB,(p-2S-RUNX2:CBFB):BGLAP geneArrowR-HSA-9008877 (Reactome)
RUNX2:CBFB,p-S451-RUNX2:CBFB,(p-2S-RUNX2:CBFB)R-HSA-9008877 (Reactome)
RUNX2:CBFB:BAX geneArrowR-HSA-9008832 (Reactome)
RUNX2:CBFB:BAX geneArrowR-HSA-9008839 (Reactome)
RUNX2:CBFB:IHH geneArrowR-HSA-8878257 (Reactome)
RUNX2:CBFB:IHH geneArrowR-HSA-8878266 (Reactome)
RUNX2:CBFB:ITGA5 geneArrowR-HSA-8939667 (Reactome)
RUNX2:CBFB:ITGA5 geneArrowR-HSA-8939670 (Reactome)
RUNX2:CBFB:ITGBL1 geneArrowR-HSA-8939829 (Reactome)
RUNX2:CBFB:ITGBL1 geneArrowR-HSA-8939833 (Reactome)
RUNX2:CBFB:LGALS3 geneArrowR-HSA-8938371 (Reactome)
RUNX2:CBFB:LGALS3 geneArrowR-HSA-8938382 (Reactome)
RUNX2:CBFB:SP7:UCMA geneArrowR-HSA-8939852 (Reactome)
RUNX2:CBFB:SP7:UCMA geneArrowR-HSA-8939870 (Reactome)
RUNX2:CBFB:p-2S-SMAD1:p-2S-SMAD1:SMAD4:SMAD6 geneArrowR-HSA-8878013 (Reactome)
RUNX2:CBFB:p-2S-SMAD1:p-2S-SMAD1:SMAD4:SMAD6 geneArrowR-HSA-8878023 (Reactome)
RUNX2:CBFB:p-2S-SMAD1:p-2S-SMAD1:SMAD4ArrowR-HSA-8877941 (Reactome)
RUNX2:CBFB:p-2S-SMAD1:p-2S-SMAD1:SMAD4R-HSA-8878013 (Reactome)
RUNX2:CBFB:p-Y-YAP1:BGLAP geneArrowR-HSA-8937869 (Reactome)
RUNX2:CBFB:p-Y-YAP1:BGLAP geneTBarR-HSA-8877922 (Reactome)
RUNX2:CBFB:p-Y-YAP1ArrowR-HSA-8937864 (Reactome)
RUNX2:CBFB:p-Y-YAP1R-HSA-8937869 (Reactome)
RUNX2:CBFBArrowR-HSA-8865425 (Reactome)
RUNX2:CBFBArrowR-HSA-9008822 (Reactome)
RUNX2:CBFBR-HSA-8877941 (Reactome)
RUNX2:CBFBR-HSA-8878257 (Reactome)
RUNX2:CBFBR-HSA-8937864 (Reactome)
RUNX2:CBFBR-HSA-8938371 (Reactome)
RUNX2:CBFBR-HSA-8939670 (Reactome)
RUNX2:CBFBR-HSA-8939833 (Reactome)
RUNX2:CBFBR-HSA-8939852 (Reactome)
RUNX2:CBFBR-HSA-8939963 (Reactome)
RUNX2:CBFBR-HSA-9008412 (Reactome)
RUNX2:CBFBR-HSA-9008832 (Reactome)
RUNX2:CBFBR-HSA-9009208 (Reactome)
RUNX2:CBFBR-HSA-9009282 (Reactome)
RUNX2:GLI3RArrowR-HSA-9008215 (Reactome)
RUNX2:HAND2ArrowR-HSA-9007816 (Reactome)
RUNX2:HDAC4ArrowR-HSA-9008326 (Reactome)
RUNX2:HDAC6ArrowR-HSA-9008389 (Reactome)
RUNX2:HEY1,HEY2,HES1ArrowR-HSA-9008177 (Reactome)
RUNX2:MAF:BGLAP geneArrowR-HSA-8877918 (Reactome)
RUNX2:MAF:BGLAP geneArrowR-HSA-8877922 (Reactome)
RUNX2:MAFArrowR-HSA-8984994 (Reactome)
RUNX2:MAFR-HSA-8877918 (Reactome)
RUNX2:RB1:BGLAP geneArrowR-HSA-8877922 (Reactome)
RUNX2:RB1:BGLAP geneArrowR-HSA-8985485 (Reactome)
RUNX2:RB1:COL1A1 geneArrowR-HSA-8985627 (Reactome)
RUNX2:RB1:COL1A1 geneArrowR-HSA-8985644 (Reactome)
RUNX2:RB1ArrowR-HSA-8985460 (Reactome)
RUNX2:RB1R-HSA-8985485 (Reactome)
RUNX2:RB1R-HSA-8985627 (Reactome)
RUNX2:RBM14ArrowR-HSA-8938356 (Reactome)
RUNX2:SATB2ArrowR-HSA-8985275 (Reactome)
RUNX2:SOX9ArrowR-HSA-8985343 (Reactome)
RUNX2:TWIST1,TWIST2ArrowR-HSA-9007860 (Reactome)
RUNX2:WWTR1(TAZ)ArrowR-HSA-2064932 (Reactome)
RUNX2:WWTR1(TAZ)R-HSA-8985227 (Reactome)
RUNX2:WWTR1:BGLAP geneArrowR-HSA-8877922 (Reactome)
RUNX2:WWTR1:BGLAP geneArrowR-HSA-8985227 (Reactome)
RUNX2:ZNF521:HDAC3ArrowR-HSA-9008137 (Reactome)
RUNX2:ZNF521:HDAC3TBarR-HSA-8877922 (Reactome)
RUNX2R-HSA-2064932 (Reactome)
RUNX2R-HSA-8865425 (Reactome)
RUNX2R-HSA-8877902 (Reactome)
RUNX2R-HSA-8938356 (Reactome)
RUNX2R-HSA-8984994 (Reactome)
RUNX2R-HSA-8985275 (Reactome)
RUNX2R-HSA-8985343 (Reactome)
RUNX2R-HSA-8985460 (Reactome)
RUNX2R-HSA-8986294 (Reactome)
RUNX2R-HSA-9007816 (Reactome)
RUNX2R-HSA-9007860 (Reactome)
RUNX2R-HSA-9008137 (Reactome)
RUNX2R-HSA-9008177 (Reactome)
RUNX2R-HSA-9008215 (Reactome)
RUNX2R-HSA-9008326 (Reactome)
RUNX2R-HSA-9008389 (Reactome)
SATB2R-HSA-8985275 (Reactome)
SMAD6 geneR-HSA-8878013 (Reactome)
SMAD6 geneR-HSA-8878023 (Reactome)
SMAD6ArrowR-HSA-8878023 (Reactome)
SOX9R-HSA-8985343 (Reactome)
SP7R-HSA-8939852 (Reactome)
TWIST1,TWIST2R-HSA-9007860 (Reactome)
UCMA geneR-HSA-8939852 (Reactome)
UCMA geneR-HSA-8939870 (Reactome)
UCMAArrowR-HSA-8939870 (Reactome)
WWTR1R-HSA-2064932 (Reactome)
YAP1R-HSA-8937820 (Reactome)
ZNF521R-HSA-9008137 (Reactome)
p-2S-RUNX2:CBFBArrowR-HSA-9009208 (Reactome)
p-2S-SMAD1:p-2S-SMAD1:SMAD4R-HSA-8877941 (Reactome)
p-S196,T198,T200-RUNX2:CBFB:MMP13 geneArrowR-HSA-8940001 (Reactome)
p-S196,T198,T200-RUNX2:CBFB:MMP13 geneArrowR-HSA-8940007 (Reactome)
p-S196,T198,T200-RUNX2:CBFBArrowR-HSA-8939963 (Reactome)
p-S196,T198,T200-RUNX2:CBFBR-HSA-8940001 (Reactome)
p-S432-RUNX2:CBFBR-HSA-9008822 (Reactome)
p-S451-RUNX2:CBFBArrowR-HSA-9008412 (Reactome)
p-S451-RUNX2:CBFBArrowR-HSA-9009282 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-9009208 (Reactome)
p-T,p-S-AKTmim-catalysisR-HSA-8939963 (Reactome)
p-Y-YAP1ArrowR-HSA-8937844 (Reactome)
p-Y-YAP1ArrowR-HSA-8937856 (Reactome)
p-Y-YAP1R-HSA-8937856 (Reactome)
p-Y-YAP1R-HSA-8937864 (Reactome)
p-Y226,Y393-ABL1ArrowR-HSA-8985227 (Reactome)

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