Signaling by TGF-beta Receptor Complex (Homo sapiens)

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355916, 38, 592830132845, 608, 31, 34, 41, 4248369, 16, 4828, 33, 39, 44, 555956382, 385210, 2027, 5245, 605, 15, 267, 483, 31, 34, 411354, 5716, 38, 592228, 4250, 532818, 2854, 57514, 4016, 38, 593652212914, 23, 24, 375154, 5747, 53306, 12, 14, 37, 49...early endosome membraneGolgi lumennucleoplasmNotecytosolcytosolDegradationearly endosomeDisassembly of Tight JunctionsDegradation of TGFBR complexK556-TGFBR2-G76-NEDD8 UBB(153-228) UBB(1-76) ARHGEF18 ADPTGFB1:p-TGFBR:ZFYVE9:p-2S-SMAD2/3p-4S,T185,T186-TGFBR1 Ubp-4S,T185,T186-TGFBR1 p-4S,T185,T186-TGFBR1 PARD3 TGFBR2 TGFB1:p-TGFBR:ZFYVE9:SMAD2/3p-4S,T185,T186-TGFBR1 PRKCZ UBB(1-76) TGFB1 UBC(77-152) RPS27A(1-76) TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7UBC(533-608) TGFBR1:FKBP1ARHOA ARHGEF18 SMAD7:SMURF2STRAP ZFYVE9-1 UBC(153-228) STRAP UBC(1-76) UBB(77-152) UBC(153-228) UBC(229-304) p-S465,S467-SMAD2 SMURF1 F11R C111-AcM-UBE2M-G76-NEDD8 CBLUBC(609-684) K567-TGFBR2-G76-NEDD8 p-S423,S425-SMAD3 PARD3 SMAD2 TGFBR2 TGFB1:p-TGFBR:STRAPp-2S-SMAD2/3:SMAD4RPS27A(1-76) TGFB1 TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4LUbUBC(77-152) UBB(153-228) TGFBR2MTMR4 SMURF1 UBB(77-152) TGFBR1 TGFB1:p-TGFBR:ZFYVE9BAMBIZFYVE9-1 F11R UBC(609-684) SMURF1 RHOA SMAD7:SMURF1SMURF1 SMAD2/3:PMEPA1XPO1SMURF2 p-4S,T185,T186-TGFBR1 TGFBR2 PARD3 NEDD4L STRAPUBC(77-152) TGFB1:TGFBR2:TGFBR1GTP SMAD7 Tight JunctionComplex:PARD6A:RHOAPMEPA1 SMAD7 RPS27A(1-76) TGFB1: TGFBR2:p-TGFBR1: BAMBI:SMAD7UBB(77-152) p-S345-PARD6A ZFYVE9-1PRKCZ TGFB1 p-S465,S467-SMAD2 UBC(609-684) TGFB1 F11R SMAD7 UBC(457-532) CGN SMAD7 p-2S-SMAD2/3:PMEPA1UBB(1-76) TGFB1 TGFB1 NEDD4L TGFBR2 TGFB1 TightJunctionComplex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOAPPP1CC SMAD7 SMURF1 FKBP1AUBC(533-608) TGFBR2 RPS27A(1-76) UBC(533-608) UBA52(1-76) Transcriptionalactivity ofSMAD2/SMAD3:SMAD4heterotrimerCGN SMAD7 NEDD4L SMURF1 UBC(1-76) UBC(381-456) TGFBR2 UBB(1-76) UBB(1-76) UBC(1-76) UBC(533-608) SMAD7 GADD34:PP1CGN SMURF1 PPP1CB ZFYVE9-1 Ub-SMAD2UBC(229-304) UBC(381-456) UBC(305-380) UBC(305-380) SMAD3TGFBR2 p-4S,T185,T186-TGFBR1 UBB(153-228) UBC(153-228) TGFB1 PiUBC(229-304) UBC(457-532) USP15 PPP1R15A UBC(229-304) p-S423,S425-SMAD3 TGFBR2 SMAD7:SMURF1UBB(153-228) SMAD7 SMURF2 RHOA PRKCZ SMAD3:STUB1p-4S,T185,T186-TGFBR1 SMAD7RPS27A(1-76) p-S423,S425-SMAD3 UBB(153-228) UBC(609-684) TGFB1 PARD3 TGFB1 SMAD3 SMAD7SMAD3 UBB(153-228) RPS27A(1-76) RHOA UBC(457-532) UBC(381-456) UBC(229-304) SMAD4UBC(153-228) SMURF/NEDD4LTGFB1 p-4S,T185,T186-TGFBR1 SMAD7:SMURF1:XPO1CGN PPP1CA TGFB1 UBB(77-152) PPP1CA PARD3 UBC(533-608) TightJunctionComplex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1UBC(609-684) TGFB1 CGN PiUBC(305-380) UBB(77-152) NEDD4LTGFBR2 UBC(305-380) PRKCZ USP15 UBC(77-152) TGFB1: p-TGFBR:I-SMAD7UBB(1-76) UBC(609-684) UBC(305-380) PMEPA1FKBP1A TightJunctionComplex:TGFBR1:PARD6A:RHOAFURINSMAD3 RPS27A(1-76) RPS27A(1-76) TGFB1: p-TGFBR:STRAP: SMAD7UBB(153-228) TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15UBB(153-228) TGFB1 SMAD3 UBC(381-456) SMAD7 UBC(305-380) PMEPA1 UBB(77-152) RPS27A(1-76) UbUBC(77-152) SMAD7 SMURF1 SMURF2 SMAD2:SMURF2UBB(153-228) SMAD7:NEDD4LUBB(1-76) TGFB1 UBC(609-684) UBC(77-152) UBC(609-684) F11R UBC(153-228) PMEPA1UBC(77-152) SMURF2 UBC(77-152) UBC(77-152) UBC(1-76) NEDD8-K556,K567-TGFBR2 TGFB1 ATPF11R UBB(77-152) Large latent complexof TGFB1UBC(1-76) UBA52(1-76) PRKCZ TGFB1 UBC(381-456) UBC(229-304) RPS27A(1-76) UBB(77-152) XPO1TGFBR1 UBA52(1-76) PPP1CB CGN SMAD7 UBA52(1-76) PRKCZ p-S345-PARD6A ATPTGFBR2 SMURF2UBC(1-76) SMAD3 RHOA G76-NEDD8-C111-AcM-UBE2M UBC(229-304) Dimeric TGFB1:TGFBR2homodimerTGFBR2 p-S465,S467-SMAD2 UBC(533-608) UBC(381-456) p-S465,S467-SMAD2 UBA52(1-76) TGFB1 UBC(457-532) UBC(381-456) SMAD7:SMURF2TGFBR2 SMURF2 UBB(1-76) ZFYVE9-1 p-4S,T185,T186-TGFBR1 UBB(153-228) p-4S,T185,T186-TGFBR1 TGFBR2 UBC(153-228) UBA52(1-76) SMAD2 UBC(153-228) Pre-TGFB1 complexBAMBI UBC(457-532) H2OGTP TGFBR2:CBLMTMR4TGFBR2 UBA52(1-76) UCHL5 F11R H2OXPO1 p-4S,T185,T186-TGFBR1 UCHL5 UBC(229-304) NEDD8-AcM-UBE2MUBA52(1-76) SMAD2 PPP1CC UBC(153-228) UBC(609-684) SMAD7 SMAD2 p-4S,T185,T186-TGFBR1 UBC(381-456) UBC(305-380) TGFBR2 UBC(153-228) H2OTGFB1 TGFBR2 SMAD2 STUB1SMAD7 AcM-UBE2MSMURF1TGFBR2 SMAD7 PARD6A FKBP1A ADPCBL SMAD4 TGFBR2 UBA52(1-76) PARD6A UBB(77-152) UBC(457-532) Neddylated TGFBR2UBC(457-532) p-S345-PARD6A SMAD2/3TGFB1 SMAD7:SMURF/NEDD4LUBC(609-684) UBC(533-608) UBC(457-532) ADPTGFB1(30-390) UBC(305-380) SMURF2 p-S465,S467-SMAD2 SMAD2TightJunctionComplex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1UBC(305-380) TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9PARD6A p-4S,T185,T186-TGFBR1 UBC(381-456) UBA52(1-76) TGFB1 TGFBR2 p-S423,S425-SMAD3 UBB(77-152) TGFBR2 ARHGEF18 PARD3 ARHGEF18 UBC(533-608) p-2S-SMAD2/3:MTMR4UBC(77-152) ARHGEF18 GTP UBB(1-76) p-2S-SMAD2/3TGFBR2 UBC(305-380) TGFB1:TGFBR2:p-TGFBR1Dimeric TGFB1UBC(153-228) UbSMAD7 TGFBR1 RHOA SMURF1SMAD7:NEDD4LPPP1R15A p-S423,S425-SMAD3 UBC(1-76) ARHGEF18 TightJunctionComplex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOAUBC(1-76) p-4S,T185,T186-TGFBR1 UBC(457-532) UBC(229-304) p-4S,T185,T186-TGFBR1 p-4S,T185,T186-TGFBR1 TGFB1 SMURF2TGFB1:TGFBR2:TGFBR1TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7STUB1 TGFBR1 UBC(1-76) UBC(533-608) ATPUb-SMAD3SMAD7 UBB(1-76) UCHL5/USP15UBC(381-456) UBC(457-532) UBC(229-304) NEDD4L NEDD4L TGFBR1 UBC(1-76) UBC(533-608) 33, 39, 44, 5517361, 11, 19, 25, 32...364638


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: 66
Reactome Author 
Reactome Author: Heldin, Carl-Henrik, Moustakas, A, Huminiecki, L, Jassal, Bijay

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