RHO GTPases activate formins (Homo sapiens)

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7, 8, 12-14, 16...1, 14, 16, 39, 41...31, 43117, 24, 5114, 16, 18, 41138, 14, 16, 19, 413035, 40, 501316, 36, 43, 6416, 18, 25, 36, 424833, 54, 631113297, 23, 24, 32, 44...26, 573048, 606, 13, 27, 38, 6111495, 10, 20, 22, 47...224, 15, 16, 19, 25...nucleoplasmendosomecytosolNUP107 NUP43 CENPC1 CENPF DIAPH3 RPS27 SKA1 Integrin cellsurfaceinteractionsAHCTF1 NUP85 BUB1 NSL1 FMNL2 GTP NDEL1 SRC-1 SPC24 GTP CENPF FMNL1 RAC1:GTP:FMNL1:Profilin:G-actinCDC20 KIF2C CENPA NDEL1 RAC1 KIF18A CKAP5 RAC1:GTP:FMNL1NUP85 FMNL1 ACTG1 FMNL3 SEH1L-1 Mg2+ MAD2L1 FMNL1ATPGDP CASC5 NDC80 PiINCENP microtubuleNUP98-5 PAFAH1B1 NUP98-5 ACTG1 SGOL2 CDC42 SKA2 CENPN RHOC:GTPNUP133 TAOK1 DIAPH1 CENPT SEH1L-1 CENPQ KIF18A NUF2 CENPE SPDL1 ppDVL:DAAM1:RHOA:GTPKNTC1 AURKB CDC42:GTP:FMNL1SRF:MKL1:SCAIRHOA:GTP:DIAPH1:EVL:Profilin:G-actinCENPK FMNL3ACTB(1-375) GTP PMF1 FMNL1 MIS12 DIAPH2-2 ACTG1 CENPP KIF2B ERCC6L SRF MAD1L1 CENPE SEH1L-1 DIAPH1 NUP160 CLASP2 SEC13 Cell junctionorganizationProfilin:G-actin:MKL1GTP DAAM1 ACTG1 XPO1 FMNL2 CLASP1 CENPQ INCENP PLK1 NUDC CENPQ KIF2C DIAPH2-3 RHOA NSL1 ZWILCH SPC24 PPP1CC SPC25 KIF2B ATP CKAP5 NUF2 RHOB:GTPRANBP2 GTP CLIP1 GTP MKL1 AURKB ITGB3BP CENPA MAPRE1 CENPL APITD1 RHOC:GTP:FMNL3:G-actinSPDL1 CENPM RHOA GTP Kinetochore:CDC42:GTP:DIAPH2-2MIS12 PMF1 ATP CENPH NUP37 MAD2L1 CLASP1 NDC80 CENPT NDC80 ATP CDC42:GTPSRGAP2 SEC13 FMNL2 CENPC1 BIRC5 ACTG1 NUP43 GTP KIF2A SRF RANGAP1 NDE1 SEH1L-1 FMNL2GTP AURKB GTP CDC42 SGOL2 CENPC1 PLK1 MKL1 CENPE APITD1 SCAINUF2 RHOA:GTPDIAPH1ZWILCH CENPE PMF1 GTP CDC20 BUB1B AURKB CENPH Profilin:G-actinRANGAP1 CLIP1 Kinetochore:CDC42:GTP:p-S196-DIAPH2-2CDC42 CDC42 DSN1 GTP CENPQ PPP1CC DIAPH2-3 MAPRE1 DIAPH2-2 CENPA GTP ACTB(1-375) BIRC5 DIAPH1,DIAPH3ITGB1MLF1IP NDEL1 DIAPH2-3CENPO NUDC B9D2 FMNL1 RHOB BUB1 NUP107 CDC42:GTP:FMNL2SPC24 MIS12 CENPM ZWINT ZW10 KIF2A MAPRE1 MAD1L1 SGOL1 RHOD CDC42 FMNL1 RHOC:GTP:FMNL2NDE1 AHCTF1 ACTG1 SEC13 ATP CENPA MAD1L1 GTP Microtubule-boundkinetochoreRHOC SRGAP2:RAC1:GTP:FMNL1:Profilin:G-actinNDC80 FMNL2 CLIP1 DIAPH2-3 CENPK DSN1 BUB3 KNTC1 Mg2+ CENPP RHOA SRF GTP SRC-1FMNL3 CENPI DIAPH1 NUP98-5 CASC5 GTP RHOC:GTP:FMNL3RHOD:GTP:DIAPH2-3RAC1:GDPCENPO SGOL1 B9D2 RHOA SGOL2 B9D2 ZW10 RHOD CENPK PAFAH1B1 KIF2C KIF2C XPO1 GTP KNTC1 ITGB3BP BUB1B ACTB(1-375) MKL1NUP85 DSN1 INCENP CDC42 CDC20 KIF18A CDCA8 SCAI ZWINT CENPM ZWILCH GTP DAAM1 NUP98-5 MAPRE1 RCC2 SRF:MKL1:ITGB1 GeneAPITD1 CENPL RCC2 MKL1MAD1L1 ACTG1 CENPN TAOK1 EVL KIF2B ATP BUB1B ADPNUP133 SPDL1 ATP MLF1IP NUP37 RHOA:GTP:Mg2+CENPF RHOC MKL1 ZWILCH GTP RAC1 beta-cateninindependent WNTsignalingBUB3 CENPN CKAP5 CLIP1 SKA1 GTP RANGAP1 ZW10 ACTG1 TAOK1 PPP1CC MLF1IP NDE1 KIF2A SPDL1 SKA2 RPS27 RHOB:GTP:DIAPH1,DIAPH3SKA1 KIF2B MLF1IP ACTB(1-375) CKAP5 SRF:MKL1CLASP1 SRFZWINT NSL1 SEC13 NUP133 CDC42:FMNL2:Profilin:G-actinGTP BUB3 AHCTF1 ITGB3BP B9D2 RANBP2 NUP133 SGOL1 CENPI MAD2L1 ACTB(1-375) RANBP2 RHOD:GTPNUP85 SKA2 RAC1 SPC25 CLASP1 BUB1 ATP CENPM ATP SPC25 ppDVL:DAAM1RHOD NUDC ITGB3BP DIAPH2-2MIS12 RAC1 RAC1:GTPSGOL1 NUF2 RHOC CDCA8 NUDC SKA1 CENPP RHOB KIF18A PMF1 DSN1 PLK1 NUP43 GTP GTP CASC5 ERCC6L ZWINT CENPH MAD2L1 BUB1 SGOL2 NUP160 APITD1 CENPL NUP160 AHCTF1 CENPI CDC42:GTPProfilinpp-DVLCENPT FMNL3 PAFAH1B1 RANGAP1 INCENP CLASP2 RCC2 CENPH ITGB1 Gene CDC42 PLK1 NDEL1 p-S196-DIAPH2-2 ITGB1 GeneCLASP2 RHOA:GTP:DIAPH1RHOC ERCC6L RHOD:GTP:DIAPH2:SRC-1RAC1 SRGAP2ACTB(1-375) CENPO ACTB(1-375) BUB3 CDC20 ERCC6L RPS27 TAOK1 RHOA DIAPH1 CASC5 CENPF SPC25 NSL1 CDCA8 CENPI SKA2 CENPT XPO1 CLASP2 DAAM1GTP MKL1 NUP107 RANBP2 CENPO XPO1 PPP1CC ZW10 EVLRPS27 ACTB(1-375) PAFAH1B1 CENPP BIRC5 NUP37 BIRC5 CDCA8 H2OKNTC1 GTP NDE1 CENPN G-actinCENPC1 RCC2 NUP107 CENPK NUP43 NUP160 KIF2A KinetochoreSPC24 EVL CENPL NUP37 BUB1B 12, 22, 4918641916, 369, 34, 46, 55, 58191112, 22, 492939, 6448, 603, 37, 45, 59, 62...1812, 22, 49302233, 54, 631316, 3611312, 16, 3616, 364813


Description

Formins are a family of proteins with 15 members in mammals, organized into 8 subfamilies. Formins are involved in the regulation of actin cytoskeleton. Many but not all formin family members are activated by RHO GTPases. Formins that serve as effectors of RHO GTPases belong to different formin subfamilies but they all share a structural similarity to Drosophila protein diaphanous and are hence named diaphanous-related formins (DRFs).

DRFs activated by RHO GTPases contain a GTPase binding domain (GBD) at their N-terminus, followed by formin homology domains 3, 1, and 2 (FH3, FH1, FH2) and a diaphanous autoregulatory domain (DAD) at the C-terminus. Most DRFs contain a dimerization domain (DD) and a coiled-coil region (CC) in between FH3 and FH1 domains (reviewed by Kuhn and Geyer 2014). RHO GTPase-activated DRFs are autoinhibited through the interaction between FH3 and DAD which is disrupted upon binding to an active RHO GTPase (Li and Higgs 2003, Lammers et al. 2005, Nezami et al. 2006). Since formins dimerize, it is not clear whether the FH3-DAD interaction is intra- or intermolecular. FH2 domain is responsible for binding to the F-actin and contributes to the formation of head-to-tail formin dimers (Xu et al. 2004). The proline-rich FH1 domain interacts with the actin-binding proteins profilins, thereby facilitating actin recruitment to formins and accelerating actin polymerization (Romero et al. 2004, Kovar et al. 2006).<p>Different formins are activated by different RHO GTPases in different cell contexts. FMNL1 (formin-like protein 1) is activated by binding to the RAC1:GTP and is involved in the formation of lamellipodia in macrophages (Yayoshi-Yamamoto et al. 2000) and is involved in the regulation of the Golgi complex structure (Colon-Franco et al. 2011). Activation of FMNL1 by CDC42:GTP contributes to the formation of the phagocytic cup (Seth et al. 2006). Activation of FMNL2 (formin-like protein 2) and FMNL3 (formin-like protein 3) by RHOC:GTP is involved in cancer cell motility and invasiveness (Kitzing et al. 2010, Vega et al. 2011). DIAPH1, activated by RHOA:GTP, promotes elongation of actin filaments and activation of SRF-mediated transcription which is inhibited by unpolymerized actin (Miralles et al. 2003). RHOF-mediated activation of DIAPH1 is implicated in formation of stress fibers (Fan et al. 2010). Activation of DIAPH1 and DIAPH3 by RHOB:GTP leads to actin coat formation around endosomes and regulates endosome motility and trafficking (Fernandez-Borja et al. 2005, Wallar et al. 2007). Endosome trafficking is also regulated by DIAPH2 transcription isoform 3 (DIAPH2-3) which, upon activation by RHOD:GTP, recruits SRC kinase to endosomes (Tominaga et al. 2000, Gasman et al. 2003). DIAPH2 transcription isoform 2 (DIAPH2-2) is involved in mitosis where, upon being activated by CDC42:GTP, it facilitates the capture of astral microtubules by kinetochores (Yasuda et al. 2004, Cheng et al. 2011). DIAPH2 is implicated in ovarian maintenance and premature ovarian failure (Bione et al. 1998). DAAM1, activated by RHOA:GTP, is involved in linking WNT signaling to cytoskeleton reorganization (Habas et al. 2001). Source:Reactome.</div>

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Bibliography

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History

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CompareRevisionActionTimeUserComment
116650view11:41, 9 May 2021EweitzModified title
114971view16:49, 25 January 2021ReactomeTeamReactome version 75
113415view11:49, 2 November 2020ReactomeTeamReactome version 74
112617view15:59, 9 October 2020ReactomeTeamReactome version 73
101533view11:40, 1 November 2018ReactomeTeamreactome version 66
101068view21:22, 31 October 2018ReactomeTeamreactome version 65
100598view19:56, 31 October 2018ReactomeTeamreactome version 64
100148view16:41, 31 October 2018ReactomeTeamreactome version 63
99698view15:10, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93766view13:34, 16 August 2017ReactomeTeamreactome version 61
93290view11:19, 9 August 2017ReactomeTeamreactome version 61
89082view07:56, 22 August 2016EgonwOntology Term : 'signaling pathway' added !
86375view09:16, 11 July 2016ReactomeTeamreactome version 56
83377view11:04, 18 November 2015ReactomeTeamVersion54
81552view13:05, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACTB(1-375) ProteinP60709 (Uniprot-TrEMBL)
ACTG1 ProteinP63261 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AHCTF1 ProteinQ8WYP5 (Uniprot-TrEMBL)
APITD1 ProteinQ8N2Z9 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
AURKB ProteinQ96GD4 (Uniprot-TrEMBL)
B9D2 ProteinQ9BPU9 (Uniprot-TrEMBL)
BIRC5 ProteinO15392 (Uniprot-TrEMBL)
BUB1 ProteinO43683 (Uniprot-TrEMBL)
BUB1B ProteinO60566 (Uniprot-TrEMBL)
BUB3 ProteinO43684 (Uniprot-TrEMBL)
CASC5 ProteinQ8NG31 (Uniprot-TrEMBL)
CDC20 ProteinQ12834 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42:FMNL2:Profilin:G-actinComplexR-HSA-5665752 (Reactome)
CDC42:GTP:FMNL1ComplexR-HSA-5665688 (Reactome)
CDC42:GTP:FMNL2ComplexR-HSA-5665735 (Reactome)
CDC42:GTPComplexR-HSA-182921 (Reactome)
CDC42:GTPComplexR-HSA-5666123 (Reactome)
CDCA8 ProteinQ53HL2 (Uniprot-TrEMBL)
CENPA ProteinP49450 (Uniprot-TrEMBL)
CENPC1 ProteinQ03188 (Uniprot-TrEMBL)
CENPE ProteinQ02224 (Uniprot-TrEMBL)
CENPF ProteinP49454 (Uniprot-TrEMBL)
CENPH ProteinQ9H3R5 (Uniprot-TrEMBL)
CENPI ProteinQ92674 (Uniprot-TrEMBL)
CENPK ProteinQ9BS16 (Uniprot-TrEMBL)
CENPL ProteinQ8N0S6 (Uniprot-TrEMBL)
CENPM ProteinQ9NSP4 (Uniprot-TrEMBL)
CENPN ProteinQ96H22 (Uniprot-TrEMBL)
CENPO ProteinQ9BU64 (Uniprot-TrEMBL)
CENPP ProteinQ6IPU0 (Uniprot-TrEMBL)
CENPQ ProteinQ7L2Z9 (Uniprot-TrEMBL)
CENPT ProteinQ96BT3 (Uniprot-TrEMBL)
CKAP5 ProteinQ14008 (Uniprot-TrEMBL)
CLASP1 ProteinQ7Z460 (Uniprot-TrEMBL)
CLASP2 ProteinO75122 (Uniprot-TrEMBL)
CLIP1 ProteinP30622 (Uniprot-TrEMBL)
Cell junction organizationPathwayR-HSA-446728 (Reactome)
DAAM1 ProteinQ9Y4D1 (Uniprot-TrEMBL)
DAAM1ProteinQ9Y4D1 (Uniprot-TrEMBL)
DIAPH1 ProteinO60610 (Uniprot-TrEMBL)
DIAPH1,DIAPH3R-HSA-5666066 (Reactome)
DIAPH1ComplexR-HSA-5665967 (Reactome)
DIAPH2-2 ProteinO60879-2 (Uniprot-TrEMBL)
DIAPH2-2ComplexR-HSA-5666139 (Reactome)
DIAPH2-3 ProteinO60879-3 (Uniprot-TrEMBL)
DIAPH2-3ComplexR-HSA-5666087 (Reactome)
DIAPH3 ProteinQ9NSV4 (Uniprot-TrEMBL)
DSN1 ProteinQ9H410 (Uniprot-TrEMBL)
ERCC6L ProteinQ2NKX8 (Uniprot-TrEMBL)
EVL ProteinQ9UI08 (Uniprot-TrEMBL)
EVLComplexR-HSA-5665986 (Reactome)
FMNL1 ProteinO95466 (Uniprot-TrEMBL)
FMNL1ComplexR-HSA-5665949 (Reactome)
FMNL2 ProteinQ96PY5 (Uniprot-TrEMBL)
FMNL2ComplexR-HSA-5665952 (Reactome)
FMNL3 ProteinQ8IVF7 (Uniprot-TrEMBL)
FMNL3ComplexR-HSA-5665954 (Reactome)
G-actinComplexR-HSA-201857 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
INCENP ProteinQ9NQS7 (Uniprot-TrEMBL)
ITGB1 Gene ProteinENSG00000150093 (ENSEMBL)
ITGB1 GeneENSG00000150093 (ENSEMBL)
ITGB1ProteinP05556 (Uniprot-TrEMBL)
ITGB3BP ProteinQ13352 (Uniprot-TrEMBL)
Integrin cell

surface

interactions		PathwayR-HSA-216083 (Reactome) The extracellular matrix (ECM) is a network of macro-molecules that underlies all epithelia and endothelia and that surrounds all connective tissue cells. This matrix provides the mechanical strength and also influences the behavior and differentiation state of cells in contact with it. The ECM are diverse in composition, but they generally comprise a mixture of fibrillar proteins, polysaccharides synthesized, secreted and organized by neighboring cells. Collagens, fibronectin, and laminins are the principal components involved in cell matrix interactions; other components, such as vitronectin, thrombospondin, and osteopontin, although less abundant, are also important adhesive molecules.
Integrins are the receptors that mediate cell adhesion to ECM. Integrins consists of one alpha and one beta subunit forming a noncovalently bound heterodimer. 18 alpha and 8 beta subunits have been identified in humans that combine to form 24 different receptors.
The integrin dimers can be broadly divided into three families consisting of the beta1, beta2/beta7, and beta3/alphaV integrins. beta1 associates with 12 alpha-subunits and can be further divided into RGD-, collagen-, or laminin binding and the related alpha4/alpha9 integrins that recognise both matrix and vascular ligands. beta2/beta7 integrins are restricted to leukocytes and mediate cell-cell rather than cell-matrix interactions, although some recognize fibrinogen. The beta3/alphaV family members are all RGD receptors and comprise aIIbb3, an important receptor on platelets, and the remaining b-subunits, which all associate with alphaV. It is the collagen receptors and leukocyte-specific integrins that contain alpha A-domains.
KIF18A ProteinQ8NI77 (Uniprot-TrEMBL)
KIF2A ProteinO00139 (Uniprot-TrEMBL)
KIF2B ProteinQ8N4N8 (Uniprot-TrEMBL)
KIF2C ProteinQ99661 (Uniprot-TrEMBL)
KNTC1 ProteinP50748 (Uniprot-TrEMBL)
Kinetochore:CDC42:GTP:DIAPH2-2ComplexR-HSA-5666131 (Reactome)
Kinetochore:CDC42:GTP:p-S196-DIAPH2-2ComplexR-HSA-5666161 (Reactome)
KinetochoreComplexR-HSA-375305 (Reactome)
MAD1L1 ProteinQ9Y6D9 (Uniprot-TrEMBL)
MAD2L1 ProteinQ13257 (Uniprot-TrEMBL)
MAPRE1 ProteinQ15691 (Uniprot-TrEMBL)
MIS12 ProteinQ9H081 (Uniprot-TrEMBL)
MKL1 ProteinQ969V6 (Uniprot-TrEMBL)
MKL1ProteinQ969V6 (Uniprot-TrEMBL)
MLF1IP ProteinQ71F23 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Microtubule-bound kinetochoreComplexR-HSA-375303 (Reactome)
NDC80 ProteinO14777 (Uniprot-TrEMBL)
NDE1 ProteinQ9NXR1 (Uniprot-TrEMBL)
NDEL1 ProteinQ9GZM8 (Uniprot-TrEMBL)
NSL1 ProteinQ96IY1 (Uniprot-TrEMBL)
NUDC ProteinQ9Y266 (Uniprot-TrEMBL)
NUF2 ProteinQ9BZD4 (Uniprot-TrEMBL)
NUP107 ProteinP57740 (Uniprot-TrEMBL)
NUP133 ProteinQ8WUM0 (Uniprot-TrEMBL)
NUP160 ProteinQ12769 (Uniprot-TrEMBL)
NUP37 ProteinQ8NFH4 (Uniprot-TrEMBL)
NUP43 ProteinQ8NFH3 (Uniprot-TrEMBL)
NUP85 ProteinQ9BW27 (Uniprot-TrEMBL)
NUP98-5 ProteinP52948-5 (Uniprot-TrEMBL)
PAFAH1B1 ProteinP43034 (Uniprot-TrEMBL)
PLK1 ProteinP53350 (Uniprot-TrEMBL)
PMF1 ProteinQ6P1K2 (Uniprot-TrEMBL)
PPP1CC ProteinP36873 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
Profilin:G-actin:MKL1ComplexR-HSA-5665995 (Reactome)
Profilin:G-actinComplexR-HSA-203080 (Reactome)
ProfilinR-HSA-203077 (Reactome)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-445010 (Reactome)
RAC1:GTP:FMNL1:Profilin:G-actinComplexR-HSA-5665660 (Reactome)
RAC1:GTP:FMNL1ComplexR-HSA-5663231 (Reactome)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RANBP2 ProteinP49792 (Uniprot-TrEMBL)
RANGAP1 ProteinP46060 (Uniprot-TrEMBL)
RCC2 ProteinQ9P258 (Uniprot-TrEMBL)
RHOA ProteinP61586 (Uniprot-TrEMBL)
RHOA:GTP:DIAPH1:EVL:Profilin:G-actinComplexR-HSA-5665977 (Reactome)
RHOA:GTP:DIAPH1ComplexR-HSA-5665988 (Reactome)
RHOA:GTP:Mg2+ComplexR-HSA-3858473 (Reactome)
RHOA:GTPComplexR-HSA-5665993 (Reactome)
RHOB ProteinP62745 (Uniprot-TrEMBL)
RHOB:GTP:DIAPH1,DIAPH3ComplexR-HSA-5666074 (Reactome)
RHOB:GTPComplexR-HSA-5666081 (Reactome)
RHOC ProteinP08134 (Uniprot-TrEMBL)
RHOC:GTP:FMNL2ComplexR-HSA-5665742 (Reactome)
RHOC:GTP:FMNL3:G-actinComplexR-HSA-5665773 (Reactome)
RHOC:GTP:FMNL3ComplexR-HSA-5665759 (Reactome)
RHOC:GTPComplexR-HSA-5665750 (Reactome)
RHOD ProteinO00212 (Uniprot-TrEMBL)
RHOD:GTP:DIAPH2-3ComplexR-HSA-5666096 (Reactome)
RHOD:GTP:DIAPH2:SRC-1ComplexR-HSA-5666105 (Reactome)
RHOD:GTPComplexR-HSA-5666092 (Reactome)
RPS27 ProteinP42677 (Uniprot-TrEMBL)
SCAI ProteinQ8N9R8 (Uniprot-TrEMBL)
SCAIProteinQ8N9R8 (Uniprot-TrEMBL)
SEC13 ProteinP55735 (Uniprot-TrEMBL)
SEH1L-1 ProteinQ96EE3-1 (Uniprot-TrEMBL)
SGOL1 ProteinQ5FBB7 (Uniprot-TrEMBL)
SGOL2 ProteinQ562F6 (Uniprot-TrEMBL)
SKA1 ProteinQ96BD8 (Uniprot-TrEMBL)
SKA2 ProteinQ8WVK7 (Uniprot-TrEMBL)
SPC24 ProteinQ8NBT2 (Uniprot-TrEMBL)
SPC25 ProteinQ9HBM1 (Uniprot-TrEMBL)
SPDL1 ProteinQ96EA4 (Uniprot-TrEMBL)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
SRF ProteinP11831 (Uniprot-TrEMBL)
SRF:MKL1:ITGB1 GeneComplexR-HSA-5666050 (Reactome)
SRF:MKL1:SCAIComplexR-HSA-5666007 (Reactome)
SRF:MKL1ComplexR-HSA-5666002 (Reactome)
SRFProteinP11831 (Uniprot-TrEMBL)
SRGAP2 ProteinO75044 (Uniprot-TrEMBL)
SRGAP2:RAC1:GTP:FMNL1:Profilin:G-actinComplexR-HSA-5665803 (Reactome)
SRGAP2ProteinO75044 (Uniprot-TrEMBL)
TAOK1 ProteinQ7L7X3 (Uniprot-TrEMBL)
XPO1 ProteinO14980 (Uniprot-TrEMBL)
ZW10 ProteinO43264 (Uniprot-TrEMBL)
ZWILCH ProteinQ9H900 (Uniprot-TrEMBL)
ZWINT ProteinO95229 (Uniprot-TrEMBL)
beta-catenin

independent WNT

signaling		PathwayR-HSA-3858494 (Reactome) Humans and mice have 19 identified WNT proteins that were originally classified as either 'canonical' or 'non-canonical' depending upon whether they were able to transform the mouse mammary epithelial cell line C57MG and to induce secondary axis formation in Xenopus (Wong et al, 1994; Du et al, 1995). So-called canonical WNTs, including Wnt1, 3, 3a and 7, initiate signaling pathways that destabilize the destruction complex and allow beta-catenin to accumulate and translocate to the nucleus where it promotes transcription (reviewed in Saito-Diaz et al, 2013). Non-canonical WNTs, including Wnt 2, 4, 5a, 5b, 6, 7b, and Wnt11 activate beta-catenin-independent responses that regulate many aspects of morphogenesis and development, often by impinging on the cytoskeleton (reviewed in van Amerongen, 2012). Two of the main beta-catenin-independent pathways are the Planar Cell Polarity (PCP) pathway, which controls the establishment of polarity in the plane of a field of cells, and the WNT/Ca2+ pathway, which promotes the release of intracellular calcium and regulates numerous downstream effectors (reviewed in Gao, 2012; De, 2011).
microtubuleR-HSA-190599 (Reactome)
p-S196-DIAPH2-2 ProteinO60879-2 (Uniprot-TrEMBL)
pp-DVLR-HSA-3858467 (Reactome)
ppDVL:DAAM1:RHOA:GTPComplexR-HSA-3858474 (Reactome)
ppDVL:DAAM1ComplexR-HSA-3858472 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-5666160 (Reactome)
ATPR-HSA-5666160 (Reactome)
CDC42:FMNL2:Profilin:G-actinArrowR-HSA-5665751 (Reactome)
CDC42:GTP:FMNL1ArrowR-HSA-5665686 (Reactome)
CDC42:GTP:FMNL2ArrowR-HSA-5665727 (Reactome)
CDC42:GTP:FMNL2R-HSA-5665751 (Reactome)
CDC42:GTPR-HSA-5665686 (Reactome)
CDC42:GTPR-HSA-5665727 (Reactome)
CDC42:GTPR-HSA-5666129 (Reactome)
DAAM1R-HSA-3858489 (Reactome)
DIAPH1,DIAPH3R-HSA-5666070 (Reactome)
DIAPH1R-HSA-5665989 (Reactome)
DIAPH2-2R-HSA-5666129 (Reactome)
DIAPH2-3R-HSA-5666088 (Reactome)
EVLR-HSA-5665982 (Reactome)
FMNL1ArrowR-HSA-5665809 (Reactome)
FMNL1R-HSA-5663232 (Reactome)
FMNL1R-HSA-5665686 (Reactome)
FMNL2R-HSA-5665727 (Reactome)
FMNL2R-HSA-5665748 (Reactome)
FMNL3R-HSA-5665761 (Reactome)
G-actinR-HSA-203070 (Reactome)
H2OR-HSA-5665809 (Reactome)
ITGB1 GeneR-HSA-5666046 (Reactome)
ITGB1 GeneR-HSA-5666049 (Reactome)
ITGB1ArrowR-HSA-5666049 (Reactome)
Kinetochore:CDC42:GTP:DIAPH2-2ArrowR-HSA-5666129 (Reactome)
Kinetochore:CDC42:GTP:DIAPH2-2R-HSA-5666160 (Reactome)
Kinetochore:CDC42:GTP:DIAPH2-2mim-catalysisR-HSA-5666160 (Reactome)
Kinetochore:CDC42:GTP:p-S196-DIAPH2-2ArrowR-HSA-5666160 (Reactome)
Kinetochore:CDC42:GTP:p-S196-DIAPH2-2ArrowR-HSA-5666169 (Reactome)
KinetochoreR-HSA-5666129 (Reactome)
KinetochoreR-HSA-5666169 (Reactome)
MKL1ArrowR-HSA-5665982 (Reactome)
MKL1ArrowR-HSA-5665999 (Reactome)
MKL1R-HSA-5665998 (Reactome)
MKL1R-HSA-5665999 (Reactome)
MKL1R-HSA-5666001 (Reactome)
Microtubule-bound kinetochoreArrowR-HSA-5666169 (Reactome)
PiArrowR-HSA-5665809 (Reactome)
Profilin:G-actin:MKL1ArrowR-HSA-5666001 (Reactome)
Profilin:G-actin:MKL1R-HSA-5665982 (Reactome)
Profilin:G-actinArrowR-HSA-203070 (Reactome)
Profilin:G-actinArrowR-HSA-5665809 (Reactome)
Profilin:G-actinR-HSA-5665659 (Reactome)
Profilin:G-actinR-HSA-5665751 (Reactome)
Profilin:G-actinR-HSA-5665767 (Reactome)
Profilin:G-actinR-HSA-5666001 (Reactome)
ProfilinR-HSA-203070 (Reactome)
R-HSA-203070 (Reactome) Profilins PFN1 and PFN2 bind to monomeric actin (G-actin), forming a 1:1 complex and subsequently regulate actin filament barbed end assembly downstream of various signaling pathways (Pring et al. 1992, Korenbaum et al. 1998, Nodelman et al. 1999)
R-HSA-3858489 (Reactome) DAAM1 (Dishevelled-associated activator of morphogenesis) is a formin-homology protein that was identified in a yeast two-hybrid screen for interactors with the DVL PDZ domain (Habas et al, 2001). FH proteins play a well-characterized role in regulating cytoskeletal reorganization (reviewed in Aspenstrom, 2010). DAAM1 contains an N-terminal GTPase binding domain (GBD), two central proline-rich FH domains and a C-terminal diaphanous autoinhibitory domain (DAD). In the absence of a WNT signal, DAAM1 exists in an autoinhibited conformation mediated by an intramolecular interaction between the DBD and DAD regions (Habas et al, 2001; Liu et al, 2007). Upon WNT signaling, a direct interaction between the DAD of DAAM1 and the PDZ domain of DVL relieves the autoinhibition. In the activated conformation, DAAM1 may undergo FH-dependent oligomerization and had been shown to recruit RHOA in a GBD-dependent manner (Habas et al, 2001; Liu et al, 2007).
R-HSA-3858495 (Reactome) Activated DAAM1 recruits RHOA to the DVL complex in a WNT-dependent manner. Activated DAAM1 is able to bind to RHOA in both the GDP and GTP bound form in vitro, but displays higher affinity for GTP-bound RHOA (Habas et al, 2001; Liu et al, 2007). Studies in Xenopus have identified a DVL-associated weak guanine exchange factor (WGEF) that promotes the exchange of GDP for GTP on RHOA and is required for WNT-PCP signaling (Tanegashima et al, 2008). Evidence suggests that a similar GEF activity is associated with the DVL-DAAM1-RHOA complex in human cells, but the protein has not been definitively identified (Habas et al, 2001; Liu et al, 2007). GTP-bound RHOA relieves the auto-inhibition of RHO-associated kinases, allowing them to dimerize and effect changes to cytoskeletal organization (reviewed in Amano et al, 2010; Lai et al, 2009). DAAM1 may also play a more direct role in regulating the cytoskeleton in response to WNT signaling, since FH domains have been shown to bind actin directly to nucleate linear actin cables (Sagot et al, 2002; Watanabe and Higashida, 2004).
R-HSA-5663232 (Reactome) FMNL1 (formin-like protein 1) binds the active, GTP-bound, form of RAC1 (Yayoshi-Yamamoto et al. 2000). Based on the sequence similarity with mouse formin Dia1, binding of RAC1:GTP relieves the autoinhibition of FMNL1 by displacing the C-terminal autoregulatory DAD domain of FMNL1 from the N-terminal FH3 domain (Rose et al. 2005, Lammers et al. 2005). As formins dimerize through their FH2 domains, it is not clear whether the autoinhibitory interaction between FH3 and DAD domains is intramolecular or intermolecular (Xu et al. 2004, Kuhn and Geyer 2014). Endogenous human FMNL1 interacts with endogenous human RAC1 in some leukemia-derived cell lines and promotes their migration (Favaro et al. 2013). FMNL1 gamma, a transcriptional isoform of FMNL1 with a DAD domain that significantly differs in sequence from DAD domains of FMNL1 transcription isoforms alpha and beta, localizes to the membrane and is active in the absence of RHO GTPase signaling. The membrane localization of FMNL1 gamma is regulated by the myristoylation of the N-terminal glycine which is triggered by an unknown mechanism (Han et al. 2009).
R-HSA-5665659 (Reactome) FMNL1, activated by binding to GTP-bound RAC1, binds actin-associated profilins PFN1 and PFN2 through the proline-rich FH1 domain of FMNL1 (Yayoshi-Yamamoto et al. 2000). The interaction with actin is achieved through the FH2 domain of FMNL1 (Romero et al. 2004, Kovar et al. 2006, Kuhn and Geyer 2014). FMNL1 and profilin-mediated reorganization of actin cytoskeleton is involved in the formation of lamellipodia, which regulates the motility of macrophages (Yayoshi-Yamamoto et al. 2000). FMNL1 was shown to regulate the structure of the Golgi complex, where different transcriptional isoforms of FMNL1 may play different roles (Colon-Franco et al. 2011).
R-HSA-5665686 (Reactome) FMNL1 binds activated CDC42 and this interaction is implicated in the phagocytic cup formation, but the precise mechanism has not been elucidated (Seth et al. 2006).
R-HSA-5665727 (Reactome) FMNL2 binds activated (GTP-bound) CDC42. FMNL2 can be myristoylated on its N-terminal glycine. Although myristoylation is not necessary for the interaction with CDC42, it contributes to FMNL2 activation. Based on the sequence similarity with mouse formin Dia1, binding of CDC42:GTP relieves the autoinhibition of FMNL2 by displacing the C-terminal autoregulatory DAD domain of FMNL2 from the N-terminal FH3 domain (Rose et al. 2005, Lammers et al. 2005). Since formins function as dimers, it is unclear whether the autoinhibitory interaction between FH3 and DAD domain is intramolecular or intermolecular (Xu et al. 2004, Kuhn and Geyer 2014). FMNL2 can also interact with RAC1 in vitro, but it seems that this interaction is not physiologically relevant (Block et al. 2012).
R-HSA-5665748 (Reactome) FMNL2 specifically interacts with the GTP-bound RHOC, which relieves FMNL2 autoinhibition and contributes to RHOC-mediated ameboid cell motility involved in cancer cell invasion (Kitzing et al. 2010). Myristoylation of the N-terminal glycine may be required for the full activation of FMNL2 (Moriya et al. 2012).
R-HSA-5665751 (Reactome) Once activated by binding to GTP-bound CDC42, FMNL2 interacts with actin bound profilin(s) and drives elongation but not nucleation of actin filaments (Block et al. 2012). The interaction between formins and profilins is achieved through the proline-rich FH1 domain of formins, while the interaction with actin is achieved through the FH2 domain of formins (Romero et al. 2004, Kovar et al. 2006, Kuhn and Geyer 2014).
R-HSA-5665761 (Reactome) FMNL3 binds activated (GTP-bound) RHOC. RHOC-mediated activation of FMNL3 promotes polarized cell migration which may be involved in cancer cell invasion (Vega et al. 2011). Myristoylation of the N-terminal glycine may be required for the full activation of FMNL3 (Moriya et al. 2012).
R-HSA-5665767 (Reactome) Activated FMNL3 (presumably associated with RHOC:GTP) has the ability to directly bind G-actin through knob and coiled-coil subdomains of the FMNL3 FH2 domain. The proline-rich FH1 domain which precedes the FH2 domain presumably interacts with profilins bound to G-actin (Romero et al. 2004, Kovar et al. 2006, Kuhn and Geyer 2014). FMNL3 contributes to the elongation of actin filaments (Heimsath and Higgs 2012, Thompson et al. 2013). Activated FMNL3 may also trigger microtubule alignment during angiogenesis (Hetheridge et al. 2012).
R-HSA-5665802 (Reactome) SRGAP2 binds FMNL1 activated by RAC1:GTP by simultaneously interacting with RAC1 and FMNL1. SRGAP2 co-localizes with RAC1, FMNL1, profilin and actin at the plasma membrane after RAC1-mediated activation of FMNL1 (Mason et al. 2011).
R-HSA-5665809 (Reactome) SRGAP2 is a GTPase activating protein that stimulates the GTPase activity of RAC1 bound to FMNL1. GTP hydrolysis produces inactive GDP-bound RAC1 which is unable to bind and activate FMNL1. SRGAP2 thereby limits the duration of FMNL1-mediated elongation of actin filaments downstream of RAC1:GTP (Mason et al. 2011).
R-HSA-5665982 (Reactome) Once activated by binding to RHOA:GTP, DIAPH1 binds profilin:G-actin complexes together with EVL (VASP) homotetramers and promotes elongation of actin filaments (Copeland and Treisman 2002, Grosse et al. 2003, Kursula et al. 2008, Breitsprecher et al. 2008). Binding of nonpolymerized actin (G-actin) to DIAPH1 and EVL releases MKL1 (MAL) transcription co-factor which is inhibited when bound to G-actin (Miralles et al. 2003).
R-HSA-5665989 (Reactome) DIAPH1 is activated by binding of the DIAPH1 dimer to GTP-bound (active) RHOA. Binding to RHOA releaves the autoinhibitory interaction of DIAPH1 FH3 and DAD domains (Otomo et al. 2005). Phosphorylation of RHOA at serine residue S188 may be required for RHOA binding to DIAPH1 (Li and Sewer 2010). The interaction between RHOA and DIAPH1 may also be positively regulated by PI3K signaling (Gao et al. 2009).
R-HSA-5665998 (Reactome) In the nucleus, MKL1 binds SRF transcription factor and enables transcription of SRF-target genes (Miralles et al. 2003).
R-HSA-5665999 (Reactome) The release of MKL1 (MAL) from nonpolymerized actin (G-actin), after profilin:G-actin complexes bind DIAPH1 and EVL (VASP) downstream of activated RHOA, enables MKL1 to translocate from the cytosol to the nucleus (Miralles et al. 2003).
R-HSA-5666001 (Reactome) MKL1 (MAL) transcription cofactor is negatively regulated by binding to nonpolymerized actin (G-actin) (Miralles et al. 2003).
R-HSA-5666008 (Reactome) SCAI forms a ternary complex with MKL1 and SRF, inhibiting the transcriptional activity of the SRF:MKL1 complex. SCAI negatively regulates cancer cell invasion facilitated by the SRF:MKL1-mediated transcription downstream of RHOA and DIAPH1, and therefore acts as a tumor suppressor (Brandt et al. 2009).
R-HSA-5666046 (Reactome) SRF:MKL1 transcription complex binds the promoter region of the integrin beta-1 (ITGB1) gene (Brandt et al. 2009).
R-HSA-5666049 (Reactome) SRF:MKL1 binding to the promoter region of the integrin beta-1 gene stimulates ITGB1 expression downstream of RHOA:GTP:DIAPH1-induced actin cytoskeleton changes. Binding of SCAI to SRF:MKL1 inhibits RHOA:GTP:DIAPH1-induced ITGB1 transcription (Brandt et al. 2009).
R-HSA-5666070 (Reactome) Activated RHOB (RHOB:GTP) recruits DIAPH1 or DIAPH3 to endosomes where they regulate actin coat formation around endosomes and endosome motility/trafficking (Fernandez-Borja et al. 2005, Wallar et al. 2007).
R-HSA-5666088 (Reactome) Activated RHOD (RHOD:GTP) binds DIAPH2 transcription isoform DIAPH2-3 (DIAPH2C) and recruits it to endosomes. RHOD and DIAPH2 regulate endosome motility through SRC-dependent regulation of actin dynamics (Gasman et al. 2003).
R-HSA-5666104 (Reactome) RHOD:GTP:DIAPH2-3 complex recruits SRC to endosomes. SRC recruitment is necessary for RHOD:GTP:DIAPH2-3-mediated regulation of endosome-associated actin cytoskeleton and endosome motility (Gasman et al. 2003). SRC directly binds to DIAPH2 (Tominaga et al. 2000).
R-HSA-5666129 (Reactome) Activated CDC42 (CDC42:GTP) can localize to kinetochores of metaphase cells and recruit DIAPH2 transcriptional isoform DIAPH2-2 (DIA-12C, mDia3) to kinetochores. The CDC42:GTP:DIAPH2-2 complex regulates the attachment of microtubules to kinetochores (Yasuda et al. 2004).
R-HSA-5666160 (Reactome) Aurora kinase B (AURKB), which is part of the kinetochore, phosphorylates DIAPH2-2 (DIA-12C, mDia3) on serine residue S196 in the FH3 (DID) domain and probably on several other residues in the FH3 and FH2 domains. AURKB-mediated phosphorylation of DIAPH2-2 is necessary for the regulation of microtubule binding to kinetochores by the CDC42:GTP:DIAPH2-2 complex (Cheng et al. 2011).
R-HSA-5666169 (Reactome) The recruitment of DIAPH2-2 (DIA-12C, mDia3) to kinetochores by activated CDC42 (CDC42:GTP) and DIAPH2-2 phosphorylation by AURKB positively regulates the attachment of microtubules to kinetochores (Yasuda et al. 2004, Cheng et al. 2011).

The human kinetochore, is a complex proteinaceous structure that assembles on centromeric DNA and mediates the association of mitotic chromosomes with spindle microtubules in prometaphase. The molecular composition of the human kinetochore is reviewed in detail in Cheeseman et al., 2008. This complex structure is composed of numerous protein complexes and networks including: the constitutive centromere-associated network (CCAN) containing several sub-networks such as (CENP-H, I, K), (CENP-50/U, O, P, Q, R), the KMN network (containing KNL1, the Mis12 complex, and the Ndc80 complex), the chromosomal passenger complex, the mitotic checkpoint complex, the nucleoporin 107-160 complex and the RZZ complex.
At prometaphase, following breakdown of the nuclear envelope, the kinetochores of condensed chromosomes begin to interact with spindle microtubules. In humans, 15-20 microtubules are bound to each kinetochore (McEwen et al., 2001), and the attachment of 15 microtubules to the kinetochore is shown in this reaction. Recently, it was found that the core kinetochore-microtubule attachment site is within the KMN network and is likely to be formed by two closely apposed low-affinity microtubule-binding sites, one in the Ndc80 complex and a second in KNL1 (Cheeseman et al., 2006).

RAC1:GDPArrowR-HSA-5665809 (Reactome)
RAC1:GTP:FMNL1:Profilin:G-actinArrowR-HSA-5665659 (Reactome)
RAC1:GTP:FMNL1:Profilin:G-actinR-HSA-5665802 (Reactome)
RAC1:GTP:FMNL1ArrowR-HSA-5663232 (Reactome)
RAC1:GTP:FMNL1R-HSA-5665659 (Reactome)
RAC1:GTPR-HSA-5663232 (Reactome)
RHOA:GTP:DIAPH1:EVL:Profilin:G-actinArrowR-HSA-5665982 (Reactome)
RHOA:GTP:DIAPH1ArrowR-HSA-5665989 (Reactome)
RHOA:GTP:DIAPH1R-HSA-5665982 (Reactome)
RHOA:GTP:Mg2+R-HSA-3858495 (Reactome)
RHOA:GTPR-HSA-5665989 (Reactome)
RHOB:GTP:DIAPH1,DIAPH3ArrowR-HSA-5666070 (Reactome)
RHOB:GTPR-HSA-5666070 (Reactome)
RHOC:GTP:FMNL2ArrowR-HSA-5665748 (Reactome)
RHOC:GTP:FMNL3:G-actinArrowR-HSA-5665767 (Reactome)
RHOC:GTP:FMNL3ArrowR-HSA-5665761 (Reactome)
RHOC:GTP:FMNL3R-HSA-5665767 (Reactome)
RHOC:GTPR-HSA-5665748 (Reactome)
RHOC:GTPR-HSA-5665761 (Reactome)
RHOD:GTP:DIAPH2-3ArrowR-HSA-5666088 (Reactome)
RHOD:GTP:DIAPH2-3R-HSA-5666104 (Reactome)
RHOD:GTP:DIAPH2:SRC-1ArrowR-HSA-5666104 (Reactome)
RHOD:GTPR-HSA-5666088 (Reactome)
SCAIR-HSA-5666008 (Reactome)
SRC-1R-HSA-5666104 (Reactome)
SRF:MKL1:ITGB1 GeneArrowR-HSA-5666046 (Reactome)
SRF:MKL1:ITGB1 GeneArrowR-HSA-5666049 (Reactome)
SRF:MKL1:SCAIArrowR-HSA-5666008 (Reactome)
SRF:MKL1:SCAITBarR-HSA-5666049 (Reactome)
SRF:MKL1ArrowR-HSA-5665998 (Reactome)
SRF:MKL1R-HSA-5666008 (Reactome)
SRF:MKL1R-HSA-5666046 (Reactome)
SRFR-HSA-5665998 (Reactome)
SRGAP2:RAC1:GTP:FMNL1:Profilin:G-actinArrowR-HSA-5665802 (Reactome)
SRGAP2:RAC1:GTP:FMNL1:Profilin:G-actinR-HSA-5665809 (Reactome)
SRGAP2:RAC1:GTP:FMNL1:Profilin:G-actinmim-catalysisR-HSA-5665809 (Reactome)
SRGAP2ArrowR-HSA-5665809 (Reactome)
SRGAP2R-HSA-5665802 (Reactome)
microtubuleR-HSA-5666169 (Reactome)
pp-DVLR-HSA-3858489 (Reactome)
ppDVL:DAAM1:RHOA:GTPArrowR-HSA-3858495 (Reactome)
ppDVL:DAAM1ArrowR-HSA-3858489 (Reactome)
ppDVL:DAAM1R-HSA-3858495 (Reactome)

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