Signaling by TGF-beta receptor complex (Homo sapiens)

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2447467232743514740, 5125, 49419, 17833, 4647, 53431, 3281, 30276, 10, 13, 14, 16...47, 483236, 392, 5051, 30471, 304626, 32, 4439, 5223435, 3715, 19, 38, 454329, 47, 54, 55, 576, 13, 20, 219, 1727, 44, 5127, 44, 5115, 19, 22, 38, 5327, 44, 51early endosomePARD3PARD6APRKCZ p-TGFBR1 PARD3p-PARD6APRKCZ Tight Junction ComplexPARD6ARHOA Tight Junction ComplexTGFB1TGFBR2p-TGFBR1p-PARD6ARHOA Tight Junction ComplexTGFB1TGFBR2p-TGFBR1p-PARD6ARHOASMURF1 TGFBR1FKBP1A TGFB1p-TGFBRSTRAP Ub p-TGFBR1 TGFBR2 homodimer SMAD7SMURF1 Dimeric TGFB1 Dimeric TGFB1 TGFBR1 homodimer TGFBR2 homodimer TGFB1TGFBR2p-TGFBR1 TGFBR2 homodimer Notep-TGFBR1 Ub p-TGFBR1 TGFBR1 homodimer p-2S-SMAD2/3 TGFB1TGFBR2p-TGFBR1 TGFB1TGFBR2p-TGFBR1 TGFBR2 homodimer Tight Junction ComplexTGFBR1PARD6ARHOA TGFBR2 homodimer nucleoplasmPARD3p-PARD6APRKCZ TGFBR1FKBP1A SMAD2/3 Dimeric TGFB1 Ub SMAD7NEDD4L DegradationSMAD2/3PMEPA1 Dimeric TGFB1 p-TGFBR1 SMAD7SMURF1XPO1 cytosolDimeric TGFB1 Dimeric TGFB1 Dimeric TGFB1 TGFBR2 homodimer TGFB1p-TGFBRSARAp-2S-SMAD2/3 PP1 catalytic subunit SMAD7SMURF/NEDD4L Dimeric TGFB1 Dimeric TGFB1 TGFB1TGFBR2p-TGFBR1 SMAD2/3 TGFBR2 homodimer p-TGFBR1 Dimeric TGFB1 TGFBR2 homodimer Dimeric TGFB1 Dimeric TGFB1TGFBR2 homodimer p-2S-SMAD2/3 TGFB1TGFBR2TGFBR1 TGFB1p-TGFBRSARASMAD2/3 Tight Junction ComplexPARD6ARHOA TGFB1TGFBR2p-TGFBR1 Dimeric TGFB1 SMAD3STUB1 p-2S-SMAD2/3 TGFBR2 homodimer Tight Junction ComplexTGFB1TGFBR2p-TGFBR1p-PARD6ARHOASMURF1 TGFB1TGFBR2p-TGFBR1Ub-SMAD7 TGFBR2 homodimer Pre-TGFB1 complex Large latent complex of TGFB1 GADD34PP1 Golgi lumenTight Junction ComplexTGFB1TGFBR2p-TGFBR1p-PARD6AUb-RHOASMURF1 TGFB1TGFBR2p-TGFBR1 Ub-SMAD3 TGFBR2 homodimer p-2S-SMAD2/3SMAD4 TGFB1p-TGFBRSARA p-TGFBR1 Dimeric TGFB1 SMURF/NEDD4L TGFB1p-TGFBRI-SMAD7GADD34PP1SARA Dimeric TGFB1 TGFB1TGFBR2p-TGFBR1 Dimeric TGFB1 p-TGFBR1 TGFBR2 homodimer TGFB1 p-TGFBR I-SMAD7 p-TGFBR1 Tight Junction ComplexTGFB1TGFBR2p-TGFBR1p-PARD6ARHOA Dimeric TGFB1 TGFBR1 homodimer SMAD7SMURF1 p-TGFBR1 Degradation of TGFBR complexTGFB1 p-TGFBR I-SMAD7 Ub p-TGFBR1 TGFBR2 homodimer TGFBR2 homodimer p-2S-SMAD2/3MTMR4 TGF-beta 1 precursor Tight Junction ComplexPARD6ARHOA TGFB1 TGFBR2 p-TGFBR1 BAMBI SMAD7 SMAD7SMURF/NEDD4L p-TGFBR1 Tight Junction Complexp-PARD6ARHOA p-TGFBR1 Tight Junction ComplexTGFB1TGFBR2p-TGFBR1p-PARD6ARHOA TGFBR2 homodimer Disassembly of Tight JunctionsTGFB1 p-TGFBR I-SMAD7 p-TGFBR1 TGFB1 p-TGFBR STRAP SMAD7 TGFB1 p-TGFBR I-SMAD7 Ub-SMAD2 Ub PARD3PARD6APRKCZ SMAD7NEDD4L PP1 catalytic subunit TGFB1 p-TGFBR I-SMAD7 TGFB1TGFBR2p-TGFBR1 TGFBR2 homodimer p-TGFBR1 Tight Junction ComplexTGFB1TGFBR2TGFBR1PARD6ARHOA PARD3p-PARD6APRKCZ Tight Junction Complexp-PARD6ARHOA TGFB1TGFBR2Ub-p-TGFBR1Ub-SMAD7 TGFBR2 homodimer Dimeric TGFB1 SMAD7SMURF2 p-2S-SMAD2/3PMEPA1 TGFB1TGFBR2TGFBR1 TGFB1TGFBR2Ub-p-TGFBR1Ub-SMAD7UCHL5/USP15 p-TGFBR1 TGFB1p-TGFBRSTRAP TGFB1TGFBR2Ub-p-TGFBR1Ub-SMAD7 UCHL5/USP15 TGFBR2 homodimer Dimeric TGFB1 Dimeric TGFB1 TGFB1TGFBR2TGFBR1 p-2S-SMAD2/3 early endosome membraneUb TGFB1TGFBR2p-TGFBR1SMAD7SMURF/NEDD4L TGFBR2 homodimer GADD34PP1 PARD3PARD6APRKCZ cytosolDimeric TGFB1 SMAD2SMURF2 TGFBR2 homodimer SMAD7SMURF1 SMAD7SMURF2 SMURF/NEDD4L Dimeric TGFB1 Tight Junction Complexp-PARD6ARHOA Transcriptional activity of SMAD2/SMAD3SMAD4 heterotrimerTGFBR2 PARD6A UBBTGFBR2 PARD3 UBCUBBPRKCZ UBCTight Junction ComplexTGFB1TGFBR2p-TGFBR1p-PARD6AUb-RHOASMURF1p-S465,S467-SMAD2 SMAD2/3Tight Junction ComplexTGFB1TGFBR2TGFBR1PARD6ARHOAUBA52ADPTGFBR2 SMAD7SMURF1p-4S,T185,T186-TGFBR1 TGFBR1 p-4S,T185,T186-TGFBR1 TGFBR2 ATPUBCp-4S,T185,T186-TGFBR1 UBCUBCTGFB1UBCUBCDimeric TGFB1TGFBR2 homodimerUBBUBCARHGEF18 p-S345-PARD6A TGFBR1 TGFBR2 p-2S-SMAD2/3NEDD4LPre-TGFB1 complexGADD34PP1TGFB1SMAD7 SMAD7NEDD4LNEDD4LUBCZFYVE9-1 BAMBI RHOA p-4S,T185,T186-TGFBR1 UBCSMAD2 UBCTGFB1 p-TGFBR STRAP SMAD7TGFB1TGFBR2TGFBR1PiPPP1R15A UBBUBCSMAD3 UBCUBA52SMURF1 UBCUBCSMAD7NEDD4LTGFBR1 UBCp-S345-PARD6A p-4S,T185,T186-TGFBR1 XPO1ARHGEF18 TGFB1SMURF1 TGFB1F11R UBCF11R TGFB1ARHGEF18 p-4S,T185,T186-TGFBR1 p-4S,T185,T186-TGFBR1 Tight Junction ComplexTGFB1TGFBR2p-TGFBR1p-PARD6ARHOASMURF1PRKCZ TGFBR2 ARHGEF18 SMURF/NEDD4LTGFB1TGFBR2p-TGFBR1F11R Ub-SMAD3UBCUBCRPS27ASMAD7 SMAD2 UBCSMAD7 TGFB1UbARHGEF18 UBCF11R SMURF2SMAD2RHOA TGFB1TGFBR2p-TGFBR1SMAD7SMURF/NEDD4LTGFB1PPP1CA RPS27AATPp-4S,T185,T186-TGFBR1 UBCTight Junction ComplexPARD6ARHOASMURF1 XPO1 FKBP1A UbUBCUBCSMAD7SMURF1ZFYVE9-1NEDD4LPRKCZ TGFBR2 PMEPA1 STUB1UBCTGFB1p-TGFBRSARAUBCUBCTGFBR2 UBCTGFB1SMURF1 UBCPPP1CA TGFB1RHOA TGFB1p-TGFBRSTRAPPPP1CC TGFB1TGFBR2TGFBR1UBCp-4S,T185,T186-TGFBR1 ZFYVE9-1 UCHL5/USP15SMAD7 SMURF1UBCUBBDimeric TGFB1p-2S-SMAD2/3PMEPA1TGFB1TGFB1 p-TGFBR I-SMAD7UBCp-4S,T185,T186-TGFBR1 RHOA TGFB1p-TGFBRI-SMAD7GADD34PP1SARATGFB1TGFB1MTMR4 UBBTGFB1UBCTGFBR2 RPS27AUCHL5 UBBSTRAPATPPPP1CB p-4S,T185,T186-TGFBR1 PMEPA1UBCSMAD7SMAD7SMURF1XPO1ZFYVE9-1 SMAD7 p-S423,S425-SMAD3 SMURF1 H2Op-4S,T185,T186-TGFBR1 TGFBR2 p-2S-SMAD2/3MTMR4PARD3 p-S423,S425-SMAD3 BAMBIUBA52ADPTGFBR2 SMAD7SMURF2MTMR4p-4S,T185,T186-TGFBR1 SMAD7SMURF/NEDD4LSMAD3 TGFB1TGFBR2p-TGFBR1Ub-SMAD7SMAD7SMURF2UbUBBUBCUBCUBBSMAD3 H2OFKBP1APMEPA1 USP15 UBCTGFBR2 UBCNEDD4Lp-4S,T185,T186-TGFBR1 TGFB1UBCSMAD3 ADPARHGEF18 SMAD4TGFBRSTRAPSMAD2 TGFB1TGFBR2Ub-p-TGFBR1Ub-SMAD7UCHL5/USP15UBBZFYVE9-1 SMURF2 STRAP NEDD4Lp-4S,T185,T186-TGFBR1 TGFBR2FURINSTUB1 RHOA TGFB1TGFBR2Ub-p-TGFBR1Ub-SMAD7PARD3 UBCPPP1R15A SMAD2SMURF2TGFBR2 RPS27AUBCPMEPA1TGFBR2 p-S465,S467-SMAD2 TGFBR2 UBCTGFBR2 SMAD2/3PMEPA1SMAD7 p-2S-SMAD2/3SMAD4SMAD2 UBCp-S345-PARD6A Tight Junction ComplexTGFBR1PARD6ARHOAp-S465,S467-SMAD2 SMURF1 TGFBR2 UBCUBCUBCFKBP1A SMURF1 SMURF2 PiPARD6A p-S423,S425-SMAD3 TGFB1p-TGFBRSARAp-2S-SMAD2/3UBBSMAD3SMAD7 p-S423,S425-SMAD3 PARD3 UBBUBBTGFBR2 UBCTGFB1SMAD7 F11R XPO1F11R TGFB1p-TGFBRSARASMAD2/3PPP1CC UBA52UBCRHOA TGFBR1FKBP1ASMURF2 PPP1CB RPS27AUBCPRKCZ UBBTGFB1UBCSMAD7 CGN TGFBR2 TGFB1PRKCZ CGN UBBUBCSMURF2TGFB1TGFB1SMAD7 SMURF2 TGFB1SMAD7SMAD7 TGFBR1 CGN CGN SMAD7 TGFB1 TGFBR2 p-TGFBR1 BAMBI SMAD7CGN SMAD4 Ub-SMAD2UBCp-S465,S467-SMAD2 CGN p-4S,T185,T186-TGFBR1 H2OTight Junction ComplexTGFB1TGFBR2p-TGFBR1p-PARD6ARHOAUBBLarge latent complex of TGFB1RPS27AUbTGFB1SMAD7 TGFBR1 SMAD3STUB1SMAD7 UBA52STRAP PARD6A PARD3 TGFB1PARD3 TGFBR2 SMURF1UBA52SMURF2 UBCSMAD7 UBBTGFB1UBCUBBPRKCZ SMAD7 5111, 12, 18, 34, 42...329, 54, 55, 57


Description

The TGF-beta/BMP pathway incorporates several signaling pathways that share most, but not all, components of a central signal transduction engine. The general signaling scheme is rather simple: upon binding of a ligand, an activated plasma membrane receptor complex is formed, which passes on the signal towards the nucleus through a phosphorylated receptor SMAD (R-SMAD). In the nucleus, the activated R-SMAD promotes transcription in complex with a closely related helper molecule termed Co-SMAD (SMAD4). However, this simple linear pathway expands into a network when various regulatory components and mechanisms are taken into account. The signaling pathway includes a great variety of different TGF-beta/BMP superfamily ligands and receptors, several types of the R-SMADs, and functionally critical negative feedback loops. The R-SMAD:Co-SMAD complex can interact with a great number of transcriptional co-activators/co-repressors to regulate positively or negatively effector genes, so that the interpretation of a signal depends on the cell-type and cross talk with other signaling pathways such as Notch, MAPK and Wnt. The pathway plays a number of different biological roles in the control of embryonic and adult cell proliferation and differentiation, and it is implicated in a great number of human diseases.
TGF beta (TGFB1) is secreted as a homodimer, and as such it binds to TGF beta receptor II (TGFBR2), inducing its dimerization. Binding of TGF beta enables TGFBR2 to form a stable hetero-tetrameric complex with TGF beta receptor I homodimer (TGFBR1). TGFBR2 acts as a serine/threonine kinase and phosphorylates serine and threonine residues within the short GS domain (glycine-serine rich domain) of TGFBR1.
The phosphorylated heterotetrameric TGF beta receptor complex (TGFBR) internalizes into clathrin coated endocytic vesicles where it associates with the endosomal membrane protein SARA. SARA facilitates the recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates recruited SMAD2 and SMAD3, inducing a conformational change that promotes formation of R-SMAD trimers and dissociation of R-SMADs from the TGF beta receptor complex.
In the cytosol, phosphorylated SMAD2 and SMAD3 associate with SMAD4 (known as Co-SMAD), forming a heterotrimer which is more stable than the R-SMAD homotrimers. R-SMAD:Co-SMAD heterotrimer translocates to the nucleus where it directly binds DNA and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation, in a context-dependent manner.
The intracellular level of SMAD2 and SMAD3 is regulated by SMURF ubiquitin ligases, which target R-SMADs for degradation. In addition, nuclear R-SMAD:Co-SMAD heterotrimer stimulates transcription of inhibitory SMADs (I-SMADs), forming a negative feedback loop. I-SMADs bind the phosphorylated TGF beta receptor complexes on caveolin coated vesicles, derived from the lipid rafts, and recruit SMURF ubiquitin ligases to TGF beta receptors, leading to ubiquitination and degradation of TGFBR1. Nuclear R-SMAD:Co-SMAD heterotrimers are targets of nuclear ubiquitin ligases which ubiquitinate SMAD2/3 and SMAD4, causing heterotrimer dissociation, translocation of ubiquitinated SMADs to the cytosol and their proteasome-mediated degradation. For a recent review of TGF-beta receptor signaling, please refer to Kang et al. 2009. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=170834

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Bibliography

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  1. Ebnet K, Suzuki A, Horikoshi Y, Hirose T, Meyer Zu Brickwedde MK, Ohno S, Vestweber D.; ''The cell polarity protein ASIP/PAR-3 directly associates with junctional adhesion molecule (JAM).''; PubMed Europe PMC Scholia
  2. Ogunjimi AA, Briant DJ, Pece-Barbara N, Le Roy C, Di Guglielmo GM, Kavsak P, Rasmussen RK, Seet BT, Sicheri F, Wrana JL.; ''Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain.''; PubMed Europe PMC Scholia
  3. Wicks SJ, Haros K, Maillard M, Song L, Cohen RE, Dijke PT, Chantry A.; ''The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling.''; PubMed Europe PMC Scholia
  4. Zhang W, Jiang Y, Wang Q, Ma X, Xiao Z, Zuo W, Fang X, Chen YG.; ''Single-molecule imaging reveals transforming growth factor-beta-induced type II receptor dimerization.''; PubMed Europe PMC Scholia
  5. Moustakas A, Lin HY, Henis YI, Plamondon J, O'Connor-McCourt MD, Lodish HF.; ''The transforming growth factor beta receptors types I, II, and III form hetero-oligomeric complexes in the presence of ligand.''; PubMed Europe PMC Scholia
  6. Bazzoni G, Martinez-Estrada OM, Orsenigo F, Cordenonsi M, Citi S, Dejana E.; ''Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin.''; PubMed Europe PMC Scholia
  7. Wrana JL, Attisano L, Cárcamo J, Zentella A, Doody J, Laiho M, Wang XF, Massagué J.; ''TGF beta signals through a heteromeric protein kinase receptor complex.''; PubMed Europe PMC Scholia
  8. Ebnet K, Aurrand-Lions M, Kuhn A, Kiefer F, Butz S, Zander K, Meyer zu Brickwedde MK, Suzuki A, Imhof BA, Vestweber D.; ''The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity.''; PubMed Europe PMC Scholia
  9. Suzuki C, Murakami G, Fukuchi M, Shimanuki T, Shikauchi Y, Imamura T, Miyazono K.; ''Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane.''; PubMed Europe PMC Scholia
  10. Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J, Yaffe MB, Zandstra PW, Wrana JL.; ''TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal.''; PubMed Europe PMC Scholia
  11. Eichhorn PJ, Rodón L, Gonzàlez-Juncà A, Dirac A, Gili M, Martínez-Sáez E, Aura C, Barba I, Peg V, Prat A, Cuartas I, Jimenez J, García-Dorado D, Sahuquillo J, Bernards R, Baselga J, Seoane J.; ''USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma.''; PubMed Europe PMC Scholia
  12. Watanabe Y, Itoh S, Goto T, Ohnishi E, Inamitsu M, Itoh F, Satoh K, Wiercinska E, Yang W, Shi L, Tanaka A, Nakano N, Mommaas AM, Shibuya H, Ten Dijke P, Kato M.; ''TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling.''; PubMed Europe PMC Scholia
  13. Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, Hu M, Davis CM, Wang J, Brunicardi FC, Shi Y, Chen YG, Meng A, Feng XH.; ''PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.''; PubMed Europe PMC Scholia
  14. Terry SJ, Zihni C, Elbediwy A, Vitiello E, Leefa Chong San IV, Balda MS, Matter K.; ''Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis.''; PubMed Europe PMC Scholia
  15. Dupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M, Martello G, Stinchfield MJ, Soligo S, Morsut L, Inui M, Moro S, Modena N, Argenton F, Newfeld SJ, Piccolo S.; ''FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination.''; PubMed Europe PMC Scholia
  16. Nakao A, Afrakhte M, Morén A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P.; ''Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling.''; PubMed Europe PMC Scholia
  17. Tang LY, Yamashita M, Coussens NP, Tang Y, Wang X, Li C, Deng CX, Cheng SY, Zhang YE.; ''Ablation of Smurf2 reveals an inhibition in TGF-β signalling through multiple mono-ubiquitination of Smad3.''; PubMed Europe PMC Scholia
  18. Kang JS, Saunier EF, Akhurst RJ, Derynck R.; ''The type I TGF-beta receptor is covalently modified and regulated by sumoylation.''; PubMed Europe PMC Scholia
  19. Leduc R, Molloy SS, Thorne BA, Thomas G.; ''Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage.''; PubMed Europe PMC Scholia
  20. Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massagué J, Niehrs C.; ''Silencing of TGF-beta signalling by the pseudoreceptor BAMBI.''; PubMed Europe PMC Scholia
  21. Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J.; ''Mechanism of activation of the TGF-beta receptor.''; PubMed Europe PMC Scholia
  22. Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL.; ''SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor.''; PubMed Europe PMC Scholia
  23. Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA, Wrana JL, Falb D.; ''The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling.''; PubMed Europe PMC Scholia
  24. Kang JS, Liu C, Derynck R.; ''New regulatory mechanisms of TGF-beta receptor function.''; PubMed Europe PMC Scholia
  25. Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K.; ''Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein.''; PubMed Europe PMC Scholia
  26. Yan X, Lin Z, Chen F, Zhao X, Chen H, Ning Y, Chen YG.; ''Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signaling.''; PubMed Europe PMC Scholia
  27. Datta PK, Moses HL.; ''STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling.''; PubMed Europe PMC Scholia
  28. Macías-Silva M, Abdollah S, Hoodless PA, Pirone R, Attisano L, Wrana JL.; ''MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling.''; PubMed Europe PMC Scholia
  29. Wang HR, Zhang Y, Ozdamar B, Ogunjimi AA, Alexandrova E, Thomsen GH, Wrana JL.; ''Regulation of cell polarity and protrusion formation by targeting RhoA for degradation.''; PubMed Europe PMC Scholia
  30. Zhang Y, Chang C, Gehling DJ, Hemmati-Brivanlou A, Derynck R.; ''Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase.''; PubMed Europe PMC Scholia
  31. Zuo W, Huang F, Chiang YJ, Li M, Du J, Ding Y, Zhang T, Lee HW, Jeong LS, Chen Y, Deng H, Feng XH, Luo S, Gao C, Chen YG.; ''c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor.''; PubMed Europe PMC Scholia
  32. Franzén P, ten Dijke P, Ichijo H, Yamashita H, Schulz P, Heldin CH, Miyazono K.; ''Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor.''; PubMed Europe PMC Scholia
  33. Zhang W, Yuan J, Yang Y, Xu L, Wang Q, Zuo W, Fang X, Chen YG.; ''Monomeric type I and type III transforming growth factor-β receptors and their dimerization revealed by single-molecule imaging.''; PubMed Europe PMC Scholia
  34. Chen YG, Liu F, Massague J.; ''Mechanism of TGFbeta receptor inhibition by FKBP12.''; PubMed Europe PMC Scholia
  35. Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL.; ''Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation.''; PubMed Europe PMC Scholia
  36. Annes JP, Munger JS, Rifkin DB.; ''Making sense of latent TGFbeta activation.''; PubMed Europe PMC Scholia
  37. Tajima Y, Goto K, Yoshida M, Shinomiya K, Sekimoto T, Yoneda Y, Miyazono K, Imamura T.; ''Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-beta signaling by Smad7.''; PubMed Europe PMC Scholia
  38. Xin H, Xu X, Li L, Ning H, Rong Y, Shang Y, Wang Y, Fu XY, Chang Z.; ''CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation.''; PubMed Europe PMC Scholia
  39. Gong L, Yeh ET.; ''Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway.''; PubMed Europe PMC Scholia
  40. Souchelnytskyi S, ten Dijke P, Miyazono K, Heldin CH.; ''Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responses.''; PubMed Europe PMC Scholia
  41. Wotton D, Lo RS, Lee S, Massagué J.; ''A Smad transcriptional corepressor.''; PubMed Europe PMC Scholia
  42. Yu J, Pan L, Qin X, Chen H, Xu Y, Chen Y, Tang H.; ''MTMR4 attenuates transforming growth factor beta (TGFbeta) signaling by dephosphorylating R-Smads in endosomes.''; PubMed Europe PMC Scholia
  43. Qin BY, Chacko BM, Lam SS, de Caestecker MP, Correia JJ, Lin K.; ''Structural basis of Smad1 activation by receptor kinase phosphorylation.''; PubMed Europe PMC Scholia
  44. Datta PK, Chytil A, Gorska AE, Moses HL.; ''Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling.''; PubMed Europe PMC Scholia
  45. Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin CH, Miyazono K, ten Dijke P.; ''TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4.''; PubMed Europe PMC Scholia
  46. Keski-Oja J, Koli K, von Melchner H.; ''TGF-beta activation by traction?''; PubMed Europe PMC Scholia
  47. Kuratomi G, Komuro A, Goto K, Shinozaki M, Miyazawa K, Miyazono K, Imamura T.; ''NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor.''; PubMed Europe PMC Scholia
  48. Chen CR, Kang Y, Siegel PM, Massagué J.; ''E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression.''; PubMed Europe PMC Scholia
  49. Souchelnytskyi S, Tamaki K, Engström U, Wernstedt C, ten Dijke P, Heldin CH.; ''Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling.''; PubMed Europe PMC Scholia
  50. Li L, Xin H, Xu X, Huang M, Zhang X, Chen Y, Zhang S, Fu XY, Chang Z.; ''CHIP mediates degradation of Smad proteins and potentially regulates Smad-induced transcription.''; PubMed Europe PMC Scholia
  51. Kawabata M, Inoue H, Hanyu A, Imamura T, Miyazono K.; ''Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors.''; PubMed Europe PMC Scholia
  52. Souchelnytskyi S, Rönnstrand L, Heldin CH, ten Dijke P.; ''Phosphorylation of Smad signaling proteins by receptor serine/threonine kinases.''; PubMed Europe PMC Scholia
  53. Wu JW, Hu M, Chai J, Seoane J, Huse M, Li C, Rigotti DJ, Kyin S, Muir TW, Fairman R, Massagué J, Shi Y.; ''Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.''; PubMed Europe PMC Scholia
  54. Chen YG, Wang Z, Ma J, Zhang L, Lu Z.; ''Endofin, a FYVE domain protein, interacts with Smad4 and facilitates transforming growth factor-beta signaling.''; PubMed Europe PMC Scholia
  55. Shi W, Sun C, He B, Xiong W, Shi X, Yao D, Cao X.; ''GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor.''; PubMed Europe PMC Scholia
  56. Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K.; ''Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation.''; PubMed Europe PMC Scholia
  57. Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL.; ''Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity.''; PubMed Europe PMC Scholia
  58. Chong PA, Lin H, Wrana JL, Forman-Kay JD.; ''Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificity.''; PubMed Europe PMC Scholia
  59. Dubois CM, Laprise MH, Blanchette F, Gentry LE, Leduc R.; ''Processing of transforming growth factor beta 1 precursor by human furin convertase.''; PubMed Europe PMC Scholia
  60. Chacko BM, Qin BY, Tiwari A, Shi G, Lam S, Hayward LJ, De Caestecker M, Lin K.; ''Structural basis of heteromeric smad protein assembly in TGF-beta signaling.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
129735view01:48, 22 May 2024EweitzModified title
115011view16:54, 25 January 2021ReactomeTeamReactome version 75
113455view11:53, 2 November 2020ReactomeTeamReactome version 74
112655view16:04, 9 October 2020ReactomeTeamReactome version 73
101571view11:43, 1 November 2018ReactomeTeamreactome version 66
101107view21:27, 31 October 2018ReactomeTeamreactome version 65
100636view20:01, 31 October 2018ReactomeTeamreactome version 64
100186view16:46, 31 October 2018ReactomeTeamreactome version 63
99736view15:12, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93936view13:46, 16 August 2017ReactomeTeamreactome version 61
93523view11:26, 9 August 2017ReactomeTeamreactome version 61
87187view08:05, 19 July 2016EgonwOntology Term : 'signaling pathway' added !
86622view09:22, 11 July 2016ReactomeTeamreactome version 56
83153view10:11, 18 November 2015ReactomeTeamVersion54
81506view13:02, 21 August 2015ReactomeTeamVersion53
76980view08:27, 17 July 2014ReactomeTeamFixed remaining interactions
76685view12:05, 16 July 2014ReactomeTeamFixed remaining interactions
76012view10:07, 11 June 2014ReactomeTeamRe-fixing comment source
75720view11:08, 10 June 2014ReactomeTeamReactome 48 Update
75072view13:58, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74717view08:47, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ARHGEF18 ProteinQ6ZSZ5 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BAMBI ProteinQ13145 (Uniprot-TrEMBL)
BAMBIProteinQ13145 (Uniprot-TrEMBL)
CGN ProteinQ9P2M7 (Uniprot-TrEMBL)
Dimeric TGFB1 TGFBR2 homodimerComplexREACT_7218 (Reactome)
Dimeric TGFB1ComplexREACT_6996 (Reactome)
F11R ProteinQ9Y624 (Uniprot-TrEMBL)
FKBP1A ProteinP62942 (Uniprot-TrEMBL)
FKBP1AProteinP62942 (Uniprot-TrEMBL)
FURINProteinP09958 (Uniprot-TrEMBL)
GADD34 PP1ComplexREACT_124291 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
Large latent complex of TGFB1ComplexREACT_7797 (Reactome)
MTMR4 ProteinQ9NYA4 (Uniprot-TrEMBL)
MTMR4ProteinQ9NYA4 (Uniprot-TrEMBL)
NEDD4LProteinQ96PU5 (Uniprot-TrEMBL)
PARD3 ProteinQ8TEW0 (Uniprot-TrEMBL)
PARD6A ProteinQ9NPB6 (Uniprot-TrEMBL)
PMEPA1 ProteinQ969W9 (Uniprot-TrEMBL)
PMEPA1ProteinQ969W9 (Uniprot-TrEMBL)
PPP1CA ProteinP62136 (Uniprot-TrEMBL)
PPP1CB ProteinP62140 (Uniprot-TrEMBL)
PPP1CC ProteinP36873 (Uniprot-TrEMBL)
PPP1R15A ProteinO75807 (Uniprot-TrEMBL)
PRKCZ ProteinQ05513 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
Pre-TGFB1 complexComplexREACT_7332 (Reactome)
RHOA ProteinP61586 (Uniprot-TrEMBL)
RPS27AProteinP62979 (Uniprot-TrEMBL)
SMAD2 SMURF2ComplexREACT_122626 (Reactome)
SMAD2 ProteinQ15796 (Uniprot-TrEMBL)
SMAD2/3 PMEPA1ComplexREACT_121843 (Reactome)
SMAD2/3ProteinREACT_7451 (Reactome)
SMAD2ProteinQ15796 (Uniprot-TrEMBL)
SMAD3 STUB1ComplexREACT_124835 (Reactome)
SMAD3 ProteinP84022 (Uniprot-TrEMBL)
SMAD3ProteinP84022 (Uniprot-TrEMBL)
SMAD4 ProteinQ13485 (Uniprot-TrEMBL)
SMAD4ProteinQ13485 (Uniprot-TrEMBL)
SMAD7 NEDD4LComplexREACT_124391 (Reactome)
SMAD7 NEDD4LComplexREACT_125398 (Reactome)
SMAD7 SMURF/NEDD4LComplexREACT_123020 (Reactome)
SMAD7

SMURF1

XPO1		ComplexREACT_122262 (Reactome)
SMAD7 SMURF1ComplexREACT_122445 (Reactome)
SMAD7 SMURF1ComplexREACT_124389 (Reactome)
SMAD7 SMURF2ComplexREACT_121453 (Reactome)
SMAD7 SMURF2ComplexREACT_124286 (Reactome)
SMAD7 ProteinO15105 (Uniprot-TrEMBL)
SMAD7ProteinO15105 (Uniprot-TrEMBL)
SMURF/NEDD4LProteinREACT_124598 (Reactome)
SMURF1 ProteinQ9HCE7 (Uniprot-TrEMBL)
SMURF1ProteinQ9HCE7 (Uniprot-TrEMBL)
SMURF2 ProteinQ9HAU4 (Uniprot-TrEMBL)
SMURF2ProteinQ9HAU4 (Uniprot-TrEMBL)
STRAP ProteinQ9Y3F4 (Uniprot-TrEMBL)
STRAPProteinQ9Y3F4 (Uniprot-TrEMBL)
STUB1 ProteinQ9UNE7 (Uniprot-TrEMBL)
STUB1ProteinQ9UNE7 (Uniprot-TrEMBL)
TGFB1 
TGFBR2
p-TGFBR1
BAMBI
SMAD7		ComplexREACT_161164 (Reactome)
TGFB1 
p-TGFBR
I-SMAD7		ComplexREACT_7842 (Reactome)
TGFB1 
p-TGFBR
STRAP
SMAD7		ComplexREACT_122595 (Reactome)
TGFB1

TGFBR2

TGFBR1		ComplexREACT_125329 (Reactome)
TGFB1

TGFBR2

TGFBR1		ComplexREACT_7425 (Reactome)
TGFB1

TGFBR2 Ub-p-TGFBR1 Ub-SMAD7

UCHL5/USP15		ComplexREACT_124446 (Reactome)
TGFB1

TGFBR2 Ub-p-TGFBR1

Ub-SMAD7		ComplexREACT_125417 (Reactome)
TGFB1

TGFBR2 p-TGFBR1 SMAD7

SMURF/NEDD4L		ComplexREACT_123560 (Reactome)
TGFB1

TGFBR2 p-TGFBR1

Ub-SMAD7		ComplexREACT_122134 (Reactome)
TGFB1

TGFBR2

p-TGFBR1		ComplexREACT_7428 (Reactome)
TGFB1

p-TGFBR I-SMAD7 GADD34 PP1

SARA		ComplexREACT_122135 (Reactome)
TGFB1

p-TGFBR SARA

SMAD2/3		ComplexREACT_7757 (Reactome)
TGFB1

p-TGFBR SARA

p-2S-SMAD2/3		ComplexREACT_6989 (Reactome)
TGFB1

p-TGFBR

SARA		ComplexREACT_7772 (Reactome)
TGFB1

p-TGFBR

STRAP		ComplexREACT_125338 (Reactome)
TGFB1ProteinP01137 (Uniprot-TrEMBL)
TGFBR STRAPComplexREACT_122598 (Reactome)
TGFBR1 FKBP1AComplexREACT_122814 (Reactome)
TGFBR1 ProteinP36897 (Uniprot-TrEMBL)
TGFBR2 ProteinP37173 (Uniprot-TrEMBL)
TGFBR2ProteinP37173 (Uniprot-TrEMBL)
Tight Junction Complex

PARD6A

RHOA		ComplexREACT_121703 (Reactome) In this complex, PARD3:PARD6A:PRKCZ is bound to JAM-A. JAM-A also binds CGN (cingulin), and CGN binds ARHGEF18, which binds RHOA. Not all components of the tight junction structure are shown.
Tight Junction Complex

TGFB1 TGFBR2 TGFBR1 PARD6A

RHOA		ComplexREACT_122365 (Reactome)
Tight Junction Complex

TGFB1 TGFBR2 p-TGFBR1 p-PARD6A RHOA

SMURF1		ComplexREACT_121985 (Reactome)
Tight Junction Complex

TGFB1 TGFBR2 p-TGFBR1 p-PARD6A

RHOA		ComplexREACT_124952 (Reactome)
Tight Junction Complex

TGFB1 TGFBR2 p-TGFBR1 p-PARD6A Ub-RHOA

SMURF1		ComplexREACT_122343 (Reactome)
Tight Junction Complex

TGFBR1 PARD6A

RHOA		ComplexREACT_124021 (Reactome)
Transcriptional activity of SMAD2/SMAD3 SMAD4 heterotrimerPathwayREACT_121061 (Reactome) In the nucleus, SMAD2/3:SMAD4 heterotrimer complex acts as a transcriptional regulator. The activity of SMAD2/3 complex is regulated both positively and negatively by association with other transcription factors (Chen et al. 2002, Varelas et al. 2008, Stroschein et al. 1999, Wotton et al. 1999). In addition, the activity of SMAD2/3:SMAD4 complex can be inhibited by nuclear protein phosphatases and ubiquitin ligases (Lin et al. 2006, Dupont et al. 2009).
UBA52ProteinP62987 (Uniprot-TrEMBL)
UBBProteinP0CG47 (Uniprot-TrEMBL)
UBCProteinP0CG48 (Uniprot-TrEMBL)
UCHL5 ProteinQ9Y5K5 (Uniprot-TrEMBL)
UCHL5/USP15ProteinREACT_122261 (Reactome)
USP15 ProteinQ9Y4E8 (Uniprot-TrEMBL)
Ub-SMAD2ComplexREACT_121470 (Reactome)
Ub-SMAD3ComplexREACT_123646 (Reactome)
UbProteinREACT_3316 (Reactome)
XPO1 ProteinO14980 (Uniprot-TrEMBL)
XPO1ProteinO14980 (Uniprot-TrEMBL)
ZFYVE9-1 ProteinO95405-1 (Uniprot-TrEMBL)
ZFYVE9-1ProteinO95405-1 (Uniprot-TrEMBL)
p-2S-SMAD2/3 MTMR4ComplexREACT_123224 (Reactome)
p-2S-SMAD2/3 PMEPA1ComplexREACT_122643 (Reactome)
p-2S-SMAD2/3 SMAD4ComplexREACT_7344 (Reactome)
p-2S-SMAD2/3ProteinREACT_7364 (Reactome)
p-4S,T185,T186-TGFBR1 ProteinP36897 (Uniprot-TrEMBL)
p-S345-PARD6A ProteinQ9NPB6 (Uniprot-TrEMBL)
p-S423,S425-SMAD3 ProteinP84022 (Uniprot-TrEMBL)
p-S465,S467-SMAD2 ProteinQ15796 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_121038 (Reactome)
ADPArrowREACT_6816 (Reactome)
ADPArrowREACT_6879 (Reactome)
ATPREACT_121038 (Reactome)
ATPREACT_6816 (Reactome)
ATPREACT_6879 (Reactome)
BAMBIREACT_160299 (Reactome)
BAMBImim-catalysisREACT_160299 (Reactome)
Dimeric TGFB1 TGFBR2 homodimerREACT_121305 (Reactome)
Dimeric TGFB1 TGFBR2 homodimerREACT_6945 (Reactome)
Dimeric TGFB1 TGFBR2 homodimermim-catalysisREACT_6945 (Reactome)
Dimeric TGFB1REACT_6872 (Reactome)
Dimeric TGFB1mim-catalysisREACT_6872 (Reactome)
FKBP1AArrowREACT_121305 (Reactome)
FKBP1AArrowREACT_6945 (Reactome)
FURINmim-catalysisREACT_6931 (Reactome)
GADD34 PP1ArrowREACT_121355 (Reactome)
GADD34 PP1REACT_121211 (Reactome)
H2OREACT_120908 (Reactome)
H2OREACT_120959 (Reactome)
H2OREACT_121355 (Reactome)
MTMR4ArrowREACT_120908 (Reactome)
MTMR4REACT_120991 (Reactome)
NEDD4LREACT_121293 (Reactome)
PMEPA1REACT_120812 (Reactome)
PMEPA1REACT_121239 (Reactome)
PiArrowREACT_120908 (Reactome)
PiArrowREACT_121355 (Reactome)
REACT_120728 (Reactome) STUB1 (CHIP), an E3 ubiquitin ligase, binds SMAD3 irrespective of TGF-beta stimulation (Li et al. 2004, Xin et al. 2005).
REACT_120732 (Reactome) STUB1 (CHIP) ubiquitinates SMAD3 in the absence of TGF-beta stimulation (Li et al. 2004, Xin et al. 2005).
REACT_120784 (Reactome) STRAP (serine-threonine kinase receptor-associated protein) is able to bind the unphosphorylated TGF-beta receptor complex. In addition, in in vitro studies, STRAP was shown to interact individually with both TGFBR1 and TGFBR2 in the absence of TGF-beta stimulation (Datta et al. 1998). This was inferred from experiments using recombinant mouse Strap with recombinant human TGF-beta receptors.
REACT_120808 (Reactome) Recruitment of SMURF1 (Ebisawa et al. 2001), SMURF2 (Kavsak et al. 2000) or NEDD4L (Kuratomi et al. 2005) to the activated TGF-beta receptor complex by SMAD7 and subsequent ubiquitination of SMAD7 and/or TGFBR1 triggers degradation of SMAD7 and TGFBR1 through proteasome and lysosome-dependent routes, resulting in downregulation of signaling by TGF-beta receptors.
REACT_120812 (Reactome) PMEPA1 binds phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimers (Watanabe et al. 2010).
REACT_120817 (Reactome) Binding of NEDD4L promotes translocation of SMAD7 to the cytosol (Kuratomi et al. 2005). This is based on experiments using recombinant mouse Smad7 and recombinant human NEDD4L.
REACT_120862 (Reactome) STRAP (serine-threonine kinase receptor-associated protein) binds to the activated TGF-beta receptor complex. In in vitro studies, STRAP is able to bind both TGFBR1 and TGFBR2 (Datta et al. 1998). This was deduced from experiments in which a recombinant mouse Strap and recombinant human TGFBR1 and TGFBR2 were expressed in COS1 cells.
REACT_120890 (Reactome) Ubiquitination of RHOA by SMURF1 leads to disassembly of tight junctions, an important step in epithelial to mesenchymal transition.
REACT_120908 (Reactome) MTMR4 protein phosphatase dephosphorylates SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimers and inhibiting transmission of TGF-beta signal to the nucleus (Yu et al. 2010).
REACT_120910 (Reactome) After SMAD7:SMURF1 complex binds to XPO1 (CRM1) through the nuclear export signal (NES) in the C-terminus of SMURF1, XPO1 enables transport of SMAD7:SMURF1 to the cytosol (Suzuki et al. 2002, Tajima et al. 2003). A recombinant mouse Smad7 and recombinant human SMURF1 were used in these experiments.
REACT_120957 (Reactome) After forming a complex in the nucleus, SMAD7:SMURF2 traffics to the cytosol (Kavsak et al. 2000). This was inferred from experiments that used a recombinant mouse Smad7 and recombinant human SMURF2.
REACT_120959 (Reactome) Ubiquitin C-terminal hydrolase UCHL5 (UCH37) deubiquitinates TGFBR1, stabilizing TGF-beta receptor complex and prolonging TGF-beta receptor signaling. Deubiqutination of SMAD7 by UCHL5 has not been examined in this context (Wicks et al. 2005). Ubiquitin peptidase USP15 also deubiquitinates and stabilizes TGFBR1, leading to enhanced signaling by TGF-beta receptor complex. USP15 does not affect the ubiquitination status of SMAD7. Amplification of USP15 has recently been reported in glioblastoma, breast and ovarian cancer. In advanced glioblastoma, TGF-beta receptor signaling acts as an oncogenic factor, and USP15-mediated upregulation of TGF-beta receptor signaling may be a key factor in glioblastoma pathogenesis (Eichhorn et al. 2012). The role of UCHL5 was inferred from experiments using recombinant mouse Uchl5 and Smad7 with recombinant human TGF-beta receptors. The role of USP15 was established by experiments using human proteins.
REACT_120979 (Reactome) Ubiquitin C-terminal hydrolase UCHL5 (UCH37) strongly binds to SMAD7 and is thereby recruited to TGF-beta receptor complex (Wicks et al. 2005). Another ubiquitin peptidase, USP15, has recently been found to associate with ubiquitinated TGFBR1 through SMAD7 (Eichhorn et al. 2012). The role of UCHL5 was inferred from experiments using recombinant mouse Uchl5 and Smad7 with recombinant human TGF-beta receptors. The role of USP15 was established by experiments with human proteins.
REACT_120991 (Reactome) A protein phosphatase MTMR4, residing in the early endosome membrane, binds phosphorylated SMAD2 and SMAD3 (Yu et al. 2010).
REACT_121029 (Reactome) TGFBR1 binds to PARD6A, a component of tight junctions, and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for interactions with PRKCZ, is necessary for binding to TGFBR1 (Ozdamar et al. 2005).
PARD6A, bound to PARD3 and PRKCZ, is associated with tight junctions through JAM-A (Ebnet et al. 2001), which is bound to CGN (cingulin) (Bazzoni et al. 2000). CGN binds ARHGEF18 (p114RhoGEF), and ARHGEF18 recruits RHOA to tight junctions. Other components of the tight junction structure are not shown in this context (Terry et al. 2011).
Junctional RHOA activity is required for maintenance of junctional integrity through regulation of actinomyosin cytoskeleton organization (Terry et al. 2011). This was inferred from experiments in which a recombinant mouse Pard6a and recombinant human TGFBR1 were studied in the context of endogenous mouse tight junctions.
REACT_121038 (Reactome) TGFBR2 recruited to tight junctions after TGF-beta stimulation phosphorylates PARD6A on serine residue S345, and it also phosphorylates TGFBR1 (Ozdamar et al. 2005). This was inferred from experiments in which a recombinant mouse Pard6a and recombinant human TGFBR1 and TGFBR2 were used.
REACT_121055 (Reactome) SMAD3, ubiquitinated by STUB1 (CHIP), is degraded in a proteasome-dependent manner. STUB1-mediated downregulation of SMAD3 level happens in the absence of TGF-beta stimulation. STUB1 may therefore keep the basal level of SMAD3 low in the absence of TGF-beta signaling (Li et al. 2004, Xin et al. 2005).
REACT_121065 (Reactome) SMAD7 binds to SMURF1 in the nucleus (Ebisawa et al. 2001, Tajima et al. 2003). SMURF1 domains WW1 and WW2, highly similar to WW2 and WW3 domains of SMURF2, are involved in SMAD7 binding. SMURF1 has two splicing isoforms. The shorter splicing isoform of SMURF1 has an inter-WW domain linker of the same length as the WW2-WW3 domain linker of SMURF2. The longer isoform of SMURF1 has a longer WW1-WW2 domain linker, resulting in decreased affinity of the longer SMURF1 isoform for SMAD7 (Chong et al. 2010). This is based on experiments with recombinant mouse Smad7 and recombinant human SMURF1.
REACT_121080 (Reactome) SMAD7 binds to phosphorylated TGFBR1 (TGF-beta receptor I), thereby recruiting SMURF1 (Ebisawa et al. 2001), SMURF2 (Kavsak et al. 2000) or NEDD4L (Kuratomi et al. 2005) ubiquitin ligases to the activated TGF-beta receptor complex. This is based on experiments in which recombinant mouse Smad7 was used together with recombinant human ubiquitin ligases and TGF-beta receptors.
REACT_121119 (Reactome) Ubiquitinated SMAD2 undergoes proteasome-dependent degradation. Therefore, SMURF2 decreases the level of SMAD2 in the cell, irrespective of TGF-beta signaling, and may regulate the competence of a cell to respond to TGF-beta signaling (Zhang et al. 2001). These findings are contradicted by a recent study of Smurf2 knockout mice, where Smad2 protein levels were found to be unaltered in the absence of Smurf2 (Tang et al. 2011).
REACT_121124 (Reactome) SMURF2, an E3 ubiquitin protein ligase, binds to SMAD7 in the nucleus. WW2 and WW3 domains of SMURF2 are both required for binding PY motif (PPXY sequence) of SMAD7. Endogenous human SMAD7 and SMURF2 were shown to form a complex in human U4A/Jak1 cells, derived from a sarcoma cell line 2fTGH. The interaction was studied in more detail by expressing tagged recombinant human SMURF2 and mouse Smad7 in human embryonic kidney cell line HEK293 (Kavsak et al. 2000, Ogunjimi et al. 2005).
REACT_121128 (Reactome) SMURF1 (Ebisawa et al. 2001), SMURF2 (Kavsak et al. 2000) or NEDD4L (Kuratomi et al. 2005) ubiquitin ligases, recruited to TGF-beta receptor complex through interaction with SMAD7, ubiquitinate both SMAD7 and/or TGF-beta receptor I (TGFBR1), targeting the complex for degradation. This was inferred from experiments using a recombinant mouse Smad7 with recombinant human ubiquitin ligases and TGF-beta receptors.
REACT_121146 (Reactome) SMURF1, recruited to tight junctions through association with phosphorylated PARD6A, ubiquitinates RHOA, leading to RHOA degradation and disassembly of tight junctions (Ozdamar et al. 2005). Disassembly of tight junctions is an important step in epithelial to mesenchymal transition. SMURF1, but not SMURF2, decreases RHOA level, and this effect is proteasome dependent (Wang et al. 2003).
REACT_121148 (Reactome) SMAD7:SMURF1 complex binds to XPO1 (CRM1) through a nuclear export signal (NES) located in the C-terminus of SMURF1 (Tajima et al. 2003). Recombinant mouse Smad7 and recombinant human SMURF1 were used in this study.
REACT_121150 (Reactome) SMURF1 ubiquitin ligase is recruited to tight junctions by binding to phosphorylated PARD6A (Ozdamar et al. 2005).
REACT_121211 (Reactome) SMAD7 recruits protein phosphatase 1 (PP1) to TGF-beta receptor complex by binding to the PP1 regulatory subunit PPP1R15A (GADD34). SARA stabilizes the complex by directly interacting with PP1 catalytic subunit, and presumably TGF-beta receptor complex (Shi et al. 2004). This was deduced based on experiments involving recombinant mouse Smad7 and recombinant human PPP1R15A, TGFBR1, TGFBR2 and SARA.
REACT_121239 (Reactome) PMEPA1 binds unphosphorylated SMAD2 and SMAD3 and prevents their phosphorylation in response to TGF-beta stimulation (Watanabe et al. 2010).
REACT_121290 (Reactome) SMURF2 binds SMAD2 irrespective of TGF-beta signaling (Zhang et al. 2001).
REACT_121293 (Reactome) NEDD4L ubiquitin ligase, structurally similar to SMURF ubiquitin ligases, binds SMAD7 (Kuratomi et al. 2005). This was inferred from experiments that used recombinant mouse Smad7 and recombinant human NEDD4L.
REACT_121305 (Reactome) After TGF-beta stimulation, TGFBR2 binds TGFBR1 anchored to tight junctions through association with PARD6A (Ozdamar et al. 2005). FKBP1A (FKBP12) prevents phosphorylation of TGFBR1 by TGFBR2 in the absence of ligand. FKBP1A dissociates from TGFBR1 after it forms a complex with ligand-activated TGFBR2 (Chen et al. 1997). This was inferred from experiments in which a recombinant mouse Pard6a and recombinant human TGFBR1 and TGFBR2 were studied in the context of endogenous mouse tight junctions.
REACT_121338 (Reactome) STRAP binds both TGF-beta receptor and SMAD7, and stabilizes interaction of phosphorylated TGF-beta receptor complex with SMAD7.This reaction may involve oligomerization of STRAP. STRAP and SMAD7 act synergistically to inhibit the transcription of TGF-beta target genes by preventing SMAD2 and SMAD3 from binding phosphorylated TGFBR1.
REACT_121355 (Reactome) PP1 dephosphorylates TGF-beta receptor-1 (TGFBR1), thereby inhibiting TGF-beta signaling. It has not been precisely examined whether PP1 dephosphorylates all TGFBR1 serine and threonine residues phosphorylated by TGFBR2 (Shi et al. 2004). This was inferred from experiments that used a recombinant mouse Smad7 and recombinant human TGFBR1, TGFBR2 and PP1.
REACT_160299 (Reactome) BAMBI (BMP and activin membrane-bound inhibitor) is a transmembrane protein closely related to TGF-beta family receptors type I, but without serine/threonine kinase activity. In Xenopus, BAMBI expression is regulated by BMP4. BAMBI interferes with BMP, activin and TGF-beta receptor complex signaling. BAMBI binds various TGF-beta type I receptors, showing the highest affinity for TGFBR1. BAMBI can also bind TGFBR2 and activin receptor type II (Onichtchouk et al. 1999). BAMBI binds SMAD7, and this interaction involves MH1 and MH2 domains of SMAD7 and the intracellular domain of BAMBI. BAMBI and SMAD7 cooperate in the repression of TGF-beta receptor complex signaling, but BAMBI-mediated recruitment of SMAD7 to activated TGF-beta receptor complex, as BAMBI preferentially binds activated TGFBR1, does not lead to TGFBR1 degradation (Yan et al. 2009). BAMBI may downregulate TGF-beta receptor complex signaling by replacing one TGFBR1 molecule in the TGF-beta receptor heterotetramer (Onichtchouk et al. 1999). Alternatively, BAMBI-mediated recruitment of SMAD7 may compete with binding of SMAD2 and SMAD3 (R-SMADs) to the activated TGF-beta receptor complex, thus interfering with the activation of R-SMADs (Yan et al. 2009).
REACT_6744 (Reactome) Upon phosphorylation of the R-SMAD (SMAD2/3), the conformation of the C-terminal (MH2) domain of the R-SMAD changes, lowering its affinity for the type I receptor and SARA. As a result, the phosphorylated R-SMAD dissociates from the activated receptor complex (TGFBR).
REACT_6760 (Reactome) The phosphorylated C-terminal tail of R-SMAD induces a conformational change in the MH2 domain (Qin et al. 2001, Chacko et al. 2004), which now acquires high affinity towards Co-SMAD i.e. SMAD4 (common mediator of signal transduction in TGF-beta/BMP signaling). The R-SMAD:Co-SMAD complex (Nakao et al. 1997) most likely is a trimer of two R-SMADs with one Co-SMAD (Kawabata et al. 1998). It is important to note that the Co-SMAD itself cannot be phosphorylated as it lacks the C-terminal serine motif.

ZFYVE16 (endofin) promotes SMAD heterotrimer formation. ZFYVE16 can bind TGFBR1 and facilitate SMAD2 phosphorylation, and it can also bind SMAD4, but the exact mechanism of ZFYVE16 (endofin) action in the context of TGF-beta receptor signaling is not known (Chen et al. 2007).
REACT_6786 (Reactome) SMAD2 is polyubiquitinated by SMURF2 and targeted for proteasome-mediated degradation.
REACT_6816 (Reactome) Formation of the hetero-tetrameric TGF-beta-1 receptor complex induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. The constitutively active type II receptor kinase (which auto-phosphorylates in the absence of ligand), trans-phosphorylates specific serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of the type I receptor (Wrana et al. 1994, Souchelnytskyi et al. 1996).

In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta-1 stimulation. Sumoylation enhances TGFBR1 function by facilitating recruitment and phosphorylation of SMAD3 (Kang et al. 2008).
REACT_6872 (Reactome) The mature dimeric TGF-beta-1 (TGFB1) binds with high affinity to its signaling receptor, the type II receptor serine/threonine kinase (TGFBR2) (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). While type II receptor can form dimeric complexes in the absence of TGFB1 when overexpressed, it predominantly exists as a monomer on the surface of unstimulated cells under physiological conditions, and dimerization of TGFBR2 is triggered by TGFB1 binding (Zhang et al. 2009).
REACT_6879 (Reactome) Activated type I receptor kinase directly phosphorylates two of the C-terminal serine residues of SMAD2 or SMAD3. Binding of these R-SMADs to the L45 loop of the type I receptor is critical for this event.
REACT_6888 (Reactome) The large latent complex (LLC) of TGF-beta-1 (TGFB1) is secreted by exocytosis to the extracellular region. TGF-beta-1 in the LLC cannot interact with the receptors and for this reason we say that it requires "activation". This means release from the LLC. This release is achieved by many mechanisms: proteolytic cleavage of the LTBPs, thrombospondin-1 binding to the LLC, integrin alphaV-beta6 binding to the LLC, reactive oxygen species and low pH. The release of mature dimeric TGF-beta-1 is essentially a mechanical process that demands cleavage and opening of the LLC structure so that the caged mature C-terminal TGF-beta-1 polypeptide is released to reach the receptor.
REACT_6909 (Reactome) I-SMADs (SMAD6 and SMAD7) reside in the nucleus presumably to be sequestered from the TGF-beta receptor complex and thus avoid inappropriate silencing of the signaling pathway. Upon activation of the signaling pathway, I-SMADs exit the nucleus and are recruited to the signaling TGF-beta receptor complex. I-SMADs directly bind to the so-called L45 loop of the type I receptor, the site of binding of R-SMADs. Thus, I-SMADs competitively inhibit the activation/phosphorylation of R-SMADs.
REACT_6923 (Reactome) The activated TGF-beta receptor complex is internalized by clathrin-mediated endocytosis into early endosomes. SARA resides in the membrane of early endosomes. Crystallographic studies suggest that dimeric SARA in the early endosome coordinates two R-SMAD molecules (SMAD2 and/or SMAD3) per one receptor complex.
REACT_6931 (Reactome) In the Golgi apparatus, TGF-beta-1 (TGFB1) is activated by furin protease cleavage of the N-terminal pro-peptide portion. This leads to the formation of the N-terminal disulphide-linked dimeric pro-peptides, also known as latency-associated proteins (LAPs) and the C-terminal mature disulphide-linked dimeric TGF-beta-1. However, the N- and C-terminal polypeptides do not physically separate. Rather they stay in one complex. In addition, the LAP forms disulphide links with separate secreted proteins, the Latent TGF-beta binding proteins (LTBPs). LTBPs-linked to LAP and the non-covalently linked mature TGF-beta-1 remain together and form the large latent complex (LLC)
REACT_6945 (Reactome) The protein complex of dimeric TGF-beta-1 with the type II receptor dimer (dimeric TGFB1:TGFBR2 homodimer) recruits the low affinity receptor, type I receptor (TGFBR1), thus forming a hetero-tetrameric receptor bound to the dimeric ligand on the extracellular face of the plasma membrane (TGFB1:TGFBR2:TGFBR1) (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase, forms a complex with TGFBR1 and prevents phosphorylation of TGFBR1 by TGFBR2 in the absence of ligand. FKBP1A dissociates from TGFBR1 after it forms a complex with ligand-activated TGFBR2 (Chen et al. 1997). TGFBR1 can homodimerize in the absence of TGFB1 when overexpressed, but under physiological conditions it exists as a monomer on the surface of unstimulated cells. TGFB1-induced dimerization of TGFBR1 is TGFBR2-dependent (Zhang et al. 2010).
SMAD2 SMURF2REACT_6786 (Reactome)
SMAD2 SMURF2mim-catalysisREACT_6786 (Reactome)
SMAD2/3ArrowREACT_120908 (Reactome)
SMAD2/3REACT_121239 (Reactome)
SMAD2/3REACT_6923 (Reactome)
SMAD2REACT_121290 (Reactome)
SMAD3 STUB1REACT_120732 (Reactome)
SMAD3 STUB1mim-catalysisREACT_120732 (Reactome)
SMAD3REACT_120728 (Reactome)
SMAD4REACT_6760 (Reactome)
SMAD7 SMURF/NEDD4LREACT_121080 (Reactome)
SMAD7

SMURF1

XPO1		mim-catalysisREACT_120910 (Reactome)
SMAD7 SMURF1ArrowREACT_120910 (Reactome)
SMAD7 SMURF1REACT_121148 (Reactome)
SMAD7ArrowREACT_121355 (Reactome)
SMAD7REACT_121065 (Reactome)
SMAD7REACT_121124 (Reactome)
SMAD7REACT_121293 (Reactome)
SMAD7REACT_121338 (Reactome)
SMAD7REACT_160299 (Reactome)
SMAD7REACT_6909 (Reactome)
SMURF/NEDD4LArrowREACT_121128 (Reactome)
SMURF1REACT_121065 (Reactome)
SMURF1REACT_121150 (Reactome)
SMURF2ArrowREACT_6786 (Reactome)
SMURF2REACT_121124 (Reactome)
SMURF2REACT_121290 (Reactome)
STRAPREACT_120784 (Reactome)
STRAPREACT_120862 (Reactome)
STUB1ArrowREACT_120732 (Reactome)
STUB1REACT_120728 (Reactome)
TGFB1 
p-TGFBR
I-SMAD7		REACT_121211 (Reactome)
TGFB1

TGFBR2

TGFBR1		ArrowREACT_121355 (Reactome)
TGFB1

TGFBR2

TGFBR1		ArrowREACT_6945 (Reactome)
TGFB1

TGFBR2

TGFBR1		REACT_120784 (Reactome)
TGFB1

TGFBR2

TGFBR1		REACT_6816 (Reactome)
TGFB1

TGFBR2

TGFBR1		mim-catalysisREACT_6816 (Reactome)
TGFB1

TGFBR2 Ub-p-TGFBR1 Ub-SMAD7

UCHL5/USP15		REACT_120959 (Reactome)
TGFB1

TGFBR2 Ub-p-TGFBR1 Ub-SMAD7

UCHL5/USP15		mim-catalysisREACT_120959 (Reactome)
TGFB1

TGFBR2 Ub-p-TGFBR1

Ub-SMAD7		ArrowREACT_121128 (Reactome)
TGFB1

TGFBR2 Ub-p-TGFBR1

Ub-SMAD7		REACT_120979 (Reactome)
TGFB1

TGFBR2 p-TGFBR1 SMAD7

SMURF/NEDD4L		REACT_121128 (Reactome)
TGFB1

TGFBR2 p-TGFBR1 SMAD7

SMURF/NEDD4L		mim-catalysisREACT_121128 (Reactome)
TGFB1

TGFBR2 p-TGFBR1

Ub-SMAD7		ArrowREACT_120959 (Reactome)
TGFB1

TGFBR2

p-TGFBR1		ArrowREACT_6816 (Reactome)
TGFB1

TGFBR2

p-TGFBR1		REACT_120862 (Reactome)
TGFB1

TGFBR2

p-TGFBR1		REACT_121080 (Reactome)
TGFB1

TGFBR2

p-TGFBR1		REACT_160299 (Reactome)
TGFB1

TGFBR2

p-TGFBR1		REACT_6909 (Reactome)
TGFB1

TGFBR2

p-TGFBR1		REACT_6923 (Reactome)
TGFB1

p-TGFBR I-SMAD7 GADD34 PP1

SARA		REACT_121355 (Reactome)
TGFB1

p-TGFBR I-SMAD7 GADD34 PP1

SARA		mim-catalysisREACT_121355 (Reactome)
TGFB1

p-TGFBR SARA

SMAD2/3		REACT_6879 (Reactome)
TGFB1

p-TGFBR SARA

SMAD2/3		mim-catalysisREACT_6879 (Reactome)
TGFB1

p-TGFBR SARA

p-2S-SMAD2/3		ArrowREACT_6879 (Reactome)
TGFB1

p-TGFBR

SARA		ArrowREACT_6744 (Reactome)
TGFB1

p-TGFBR

STRAP		REACT_121338 (Reactome)
TGFBR1 FKBP1AREACT_121029 (Reactome)
TGFBR1 FKBP1AREACT_6945 (Reactome)
TGFBR2REACT_6872 (Reactome)
Tight Junction Complex

PARD6A

RHOA		REACT_121029 (Reactome)
Tight Junction Complex

TGFB1 TGFBR2 TGFBR1 PARD6A

RHOA		ArrowREACT_121305 (Reactome)
Tight Junction Complex

TGFB1 TGFBR2 TGFBR1 PARD6A

RHOA		REACT_121038 (Reactome)
Tight Junction Complex

TGFB1 TGFBR2 p-TGFBR1 p-PARD6A RHOA

SMURF1		REACT_121146 (Reactome)
Tight Junction Complex

TGFB1 TGFBR2 p-TGFBR1 p-PARD6A

RHOA		ArrowREACT_121038 (Reactome)
Tight Junction Complex

TGFB1 TGFBR2 p-TGFBR1 p-PARD6A

RHOA		REACT_121150 (Reactome)
Tight Junction Complex

TGFBR1 PARD6A

RHOA		REACT_121305 (Reactome)
UCHL5/USP15ArrowREACT_120959 (Reactome)
UCHL5/USP15REACT_120979 (Reactome)
Ub-SMAD2ArrowREACT_6786 (Reactome)
Ub-SMAD3ArrowREACT_120732 (Reactome)
UbArrowREACT_120959 (Reactome)
UbREACT_120732 (Reactome)
UbREACT_121128 (Reactome)
UbREACT_121146 (Reactome)
UbREACT_6786 (Reactome)
XPO1ArrowREACT_120910 (Reactome)
XPO1REACT_121148 (Reactome)
ZFYVE9-1ArrowREACT_121355 (Reactome)
ZFYVE9-1REACT_121211 (Reactome)
ZFYVE9-1REACT_6923 (Reactome)
ZFYVE9-1mim-catalysisREACT_6923 (Reactome)
p-2S-SMAD2/3 MTMR4REACT_120908 (Reactome)
p-2S-SMAD2/3 MTMR4mim-catalysisREACT_120908 (Reactome)
p-2S-SMAD2/3ArrowREACT_6744 (Reactome)
p-2S-SMAD2/3REACT_120812 (Reactome)
p-2S-SMAD2/3REACT_120991 (Reactome)
p-2S-SMAD2/3REACT_6760 (Reactome)
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