Signaling by TGF-beta Receptor Complex (Homo sapiens)

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2436, 4638, 50122, 353117, 30574237, 56, 585538, 5035, 47, 563129, 5736, 59473, 113543, 45, 51, 53, 54, 6016, 23574, 5, 7, 322718, 21, 4028, 45, 49, 604234, 57303735, 47, 5638, 5035, 47, 565744221, 6, 8, 14, 5712305, 7, 32-34529, 373, 115520, 2647DegradationDisassembly of Tight Junctionsearly endosomeDegradation of TGFBR complexnucleoplasmcytosolGolgi lumencytosolearly endosome membraneNoteTight JunctionComplex:PARD6A:RHOAUSP15 TGFBR2 UBC(457-532) SMURF1 UBC(77-152) UbTGFB1 p-S423,S425-SMAD3 UBA52(1-76) PPP1R15A p-4S,T185,T186-TGFBR1 UBC(609-684) SMAD7:SMURF1UbUBC(381-456) RPS27A(1-76) RHOA SMURF1 CBLp-4S,T185,T186-TGFBR1 SMAD7 SMURF2p-S423,S425-SMAD3 ADPH2OPPP1CA UBB(77-152) SMAD7:SMURF1:XPO1RPS27A(1-76) SMAD7SMURF2 TightJunctionComplex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOATGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15UBB(153-228) SMURF1 ADPTGFBR1:FKBP1AARHGEF18 UBC(305-380) SMAD3 TGFBR2 UBB(153-228) UBC(381-456) XPO1 UBC(533-608) F11R UBC(153-228) SMAD7 ADPUBC(533-608) GTP UBC(457-532) CBL RPS27A(1-76) TGFB1:TGFBR2:TGFBR1PARD3 UBC(609-684) SMAD7:SMURF1UBC(229-304) TGFB1: TGFBR2:p-TGFBR1: BAMBI:SMAD7SMAD4UBC(305-380) PRKCZ UBC(1-76) RPS27A(1-76) SMURF1 F11R ATPFKBP1A PMEPA1RPS27A(1-76) UBB(1-76) TGFBR2 TGFBR2 TGFB1 SMAD7 F11R SMAD3:STUB1SMAD7 TGFBR2 UBB(153-228) PRKCZ UBA52(1-76) p-S465,S467-SMAD2 XPO1ARHGEF18 p-4S,T185,T186-TGFBR1 p-2S-SMAD2/3:SMAD4TGFB1 SMURF/NEDD4LPARD3 TGFBR1 NEDD4L NEDD4L SMAD7 CGN UBC(457-532) Dimeric TGFB1TGFBR2 UBA52(1-76) UBC(533-608) SMAD7 UBB(1-76) UBC(381-456) TGFBR1 GTP H2OUBB(153-228) STRAPTGFBR2 UBC(457-532) ZFYVE9-1 TGFB1 ZFYVE9-1 ZFYVE9-1 TGFBR2 SMURF2UBC(533-608) TightJunctionComplex:TGFBR1:PARD6A:RHOAUBC(533-608) PMEPA1 TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7TGFB1 UBB(77-152) SMAD7:NEDD4LUBC(609-684) UBC(305-380) UbTGFB1: p-TGFBR:I-SMAD7UBC(609-684) ZFYVE9-1 UBB(77-152) PPP1CB GTP PPP1CA UBC(381-456) UBC(381-456) SMURF2 TGFB1: p-TGFBR:STRAP: SMAD7SMAD7 RPS27A(1-76) p-4S,T185,T186-TGFBR1 TGFB1(30-390) UBB(153-228) UBC(77-152) SMAD7:SMURF2UBB(1-76) TGFBR2 UBB(153-228) TGFB1 C111-AcM-UBE2M-G76-NEDD8 K556-TGFBR2-G76-NEDD8 UBC(229-304) PARD3 SMAD7 NEDD4L UBC(533-608) NEDD4L UBC(153-228) RHOA PMEPA1UBC(77-152) UBC(305-380) p-4S,T185,T186-TGFBR1 PPP1CC TGFBR2:CBLSTUB1 UBB(77-152) SMAD7 UBC(381-456) p-S345-PARD6A TGFBR2 UBC(381-456) UBA52(1-76) UCHL5 UBC(1-76) UBC(77-152) TGFB1 UBB(1-76) NEDD4LRHOA TGFB1 UBC(381-456) p-S423,S425-SMAD3 UBC(77-152) p-S465,S467-SMAD2 SMAD3 UBC(305-380) ARHGEF18 UBB(77-152) SMAD2:SMURF2p-S465,S467-SMAD2 UBC(381-456) UCHL5/USP15PARD3 TGFB1 TGFB1 UBC(153-228) UBC(153-228) TGFB1 TGFBR2 p-4S,T185,T186-TGFBR1 UBC(305-380) TGFBR2 UBC(229-304) TGFB1:p-TGFBR:STRAPG76-NEDD8-C111-AcM-UBE2M PARD6A Large latent complexof TGFB1TGFBR2 UBC(1-76) TGFB1 SMURF1 p-S345-PARD6A TGFBR2 SMURF2 UBC(77-152) SMAD2TGFBR2 p-4S,T185,T186-TGFBR1 UBA52(1-76) SMAD2/3:PMEPA1PiUBC(533-608) UBB(153-228) UBB(1-76) UBC(1-76) UBB(1-76) SMAD3 GADD34:PP1SMAD7 SMURF2 UBB(153-228) PRKCZ UBC(457-532) UBA52(1-76) F11R UBB(1-76) FKBP1A SMAD7:SMURF2Dimeric TGFB1:TGFBR2homodimerARHGEF18 SMAD7 p-4S,T185,T186-TGFBR1 p-2S-SMAD2/3RPS27A(1-76) CGN SMAD7:NEDD4Lp-S423,S425-SMAD3 TGFB1 TGFBR2 p-4S,T185,T186-TGFBR1 UBC(153-228) RPS27A(1-76) SMAD3 p-2S-SMAD2/3:PMEPA1UBC(153-228) Transcriptionalactivity ofSMAD2/SMAD3:SMAD4heterotrimerTGFBR2 UBC(229-304) SMURF1 TightJunctionComplex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOANEDD8-AcM-UBE2MSMAD7 F11R UBA52(1-76) CGN SMAD2/3p-S465,S467-SMAD2 RHOA UBC(457-532) p-4S,T185,T186-TGFBR1 UCHL5 UBC(153-228) PRKCZ PRKCZ TGFBR2 BAMBI SMAD2 UBC(457-532) UBC(229-304) NEDD8-K556,K567-TGFBR2 CGN Neddylated TGFBR2UBC(229-304) p-4S,T185,T186-TGFBR1 UBB(1-76) TGFB1:p-TGFBR:ZFYVE9:p-2S-SMAD2/3UBB(153-228) MTMR4 SMAD7:SMURF/NEDD4LTGFBR1 p-S345-PARD6A ARHGEF18 UBC(1-76) PARD3 SMURF1 UBC(609-684) TGFB1 TightJunctionComplex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1NEDD4L TGFBR2 H2OTGFBR2RPS27A(1-76) Ub-SMAD2UBB(77-152) PPP1CB UBC(305-380) p-4S,T185,T186-TGFBR1 PPP1R15A TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4LCGN UBA52(1-76) SMAD4 UBC(1-76) TGFB1 UBC(533-608) UBC(153-228) UBB(77-152) p-S465,S467-SMAD2 p-4S,T185,T186-TGFBR1 UBA52(1-76) RPS27A(1-76) PPP1CC UBC(533-608) UBB(77-152) UBC(229-304) UBB(77-152) MTMR4K567-TGFBR2-G76-NEDD8 SMAD7SMURF2 TGFB1 XPO1TGFB1 SMAD2 TGFBR1 BAMBIUBC(153-228) UBC(457-532) SMURF1UBC(609-684) UBC(305-380) STRAP RHOA UBB(153-228) TGFB1:TGFBR2:p-TGFBR1UBC(609-684) FURINUBB(77-152) TGFB1:TGFBR2:TGFBR1UBB(1-76) ZFYVE9-1p-2S-SMAD2/3:MTMR4UBC(77-152) TGFB1:p-TGFBR:ZFYVE9:SMAD2/3UBC(229-304) UBC(1-76) UBC(609-684) TGFB1:p-TGFBR:ZFYVE9TGFBR2 p-4S,T185,T186-TGFBR1 UBC(533-608) UBC(457-532) ATPUBC(609-684) UBC(1-76) SMAD7 CGN AcM-UBE2MSMAD3UBC(457-532) TGFB1 p-4S,T185,T186-TGFBR1 ARHGEF18 TGFB1 UBC(1-76) TGFBR1 SMAD7 SMAD7 USP15 PARD6A SMURF1FKBP1APRKCZ SMURF2 PiTGFB1 p-S423,S425-SMAD3 UBC(381-456) STRAP TGFB1 UBC(77-152) PMEPA1 Pre-TGFB1 complexSMAD2 SMAD2 RHOA PARD6A PARD3 TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9UBC(305-380) UBC(609-684) TGFBR2 SMAD7 UBC(153-228) F11R TightJunctionComplex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1UbATPUBC(1-76) UBC(77-152) SMURF1 UBB(1-76) UBA52(1-76) TGFB1 UBC(77-152) SMAD2 UBC(229-304) TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7SMAD3 STUB1p-4S,T185,T186-TGFBR1 UBC(305-380) UBC(229-304) Ub-SMAD310, 13, 15, 25, 41...313935191, 6, 8, 1431


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. View original pathway at Reactome.


Pathway is converted from Reactome ID: 170834
Reactome version: 75
Reactome Author 
Reactome Author: Heldin, Carl-Henrik, Moustakas, A, Huminiecki, L, Jassal, Bijay

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