Signaling by TGF-beta receptor complex (Homo sapiens)

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475713, 3222135, 23, 50543028, 407, 24, 443, 26, 44319562437, 531511, 342, 10, 31, 46162218, 33, 42, 5926571, 1926153, 26, 443, 1237, 53138, 9, 19, 49, 5114, 38193, 26, 445610, 21, 43, 46, 52...37, 5319, 391, 18, 33, 41, 5924, 3614, 3819620, 3417, 58Golgi lumenearly endosome membraneNoteDegradationnucleoplasmearly endosomeDegradation of TGFBR complexcytosolDisassembly of Tight JunctionscytosolUBC(305-380) SMURF1PPP1CA TGFB1 p-4S,T185,T186-TGFBR1 USP15 UBC(77-152) TGFBR2 F11R TGFB1 SMAD7 TGFB1 TGFB1:TGFBR2:TGFBR1UBA52(1-76) p-S345-PARD6A p-4S,T185,T186-TGFBR1 p-S465,S467-SMAD2 TGFB1 TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7UBC(609-684) SMAD7 p-4S,T185,T186-TGFBR1 UbSMAD2 p-4S,T185,T186-TGFBR1 TGFBR2 ARHGEF18 UBC(457-532) TGFB1 TightJunctionComplex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1TGFBR2 SMAD7 XPO1UBC(153-228) PARD3 TGFBR2 p-S423,S425-SMAD3 UBB(1-76) PMEPA1F11R UBB(153-228) p-4S,T185,T186-TGFBR1 UBC(457-532) NEDD4LTGFBR2 UBA52(1-76) UBC(533-608) SMAD4 STRAPRPS27A(1-76) SMAD3RHOA ZFYVE9-1 F11R SMAD2 ATPSMURF1 UBC(77-152) UbUBC(1-76) UBC(533-608) UBC(77-152) UBB(77-152) UBC(1-76) SMAD7 UBC(381-456) SMAD7 RHOA SMAD3 TGFB1:TGFBR2:TGFBR1ARHGEF18 UBE2MDimeric TGFB1:TGFBR2homodimerARHGEF18 TGFBR2 SMURF2UBC(153-228) TGFBR1:FKBP1APMEPA1TGFB1 PPP1CC UBB(1-76) UBB(1-76) NEDD8-K556,K567-TGFBR2 PRKCZ UBC(153-228) RPS27A(1-76) TGFB1: p-TGFBR:STRAP: SMAD7Neddylated TGFBR2TGFB1 UBC(305-380) p-S465,S467-SMAD2 STRAP SMAD7:SMURF2p-2S-SMAD2/3:PMEPA1PARD6A UBC(381-456) TGFBR2 STRAP UBC(305-380) TightJunctionComplex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOASMAD3 UBC(229-304) UbSMURF1Ub-SMAD2p-S465,S467-SMAD2 p-4S,T185,T186-TGFBR1 ADPARHGEF18 CGN FKBP1A TGFB1:p-TGFBR:ZFYVE9:SMAD2/3F11R TGFBR2 SMURF1 TGFBR2 CBLp-4S,T185,T186-TGFBR1 CGN CGN UBC(533-608) TGFB1 TGFB1 RHOA SMAD7:SMURF1UBB(77-152) UBC(457-532) ZFYVE9-1TGFB1 UBC(609-684) RPS27A(1-76) PARD3 SMURF1 SMAD7 ARHGEF18 p-S465,S467-SMAD2 TGFB1:p-TGFBR:ZFYVE9:p-2S-SMAD2/3p-4S,T185,T186-TGFBR1 Tight JunctionComplex:PARD6A:RHOATGFBR2 UBC(381-456) K567-TGFBR2-G76-NEDD8 SMAD7 TGFBR2SMAD7:SMURF/NEDD4LARHGEF18 UBC(609-684) TGFB1 TGFB1 SMURF1 PPP1CB ADPGADD34:PP1UBB(153-228) UBB(77-152) PARD3 UBA52(1-76) SMAD2:SMURF2UBC(609-684) NEDD8-C111-UBE2M UBB(77-152) UCHL5/USP15SMURF2 p-4S,T185,T186-TGFBR1 TGFB1 TGFBR2 TGFB1 ATPTightJunctionComplex:TGFBR1:PARD6A:RHOASMAD7 SMAD7:SMURF1TGFBR1 ATPNEDD4L PARD6A SMURF2 TGFB1 TightJunctionComplex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOASMAD3 PRKCZ ZFYVE9-1 TGFB1(30-390) SMAD7 SMURF/NEDD4LTGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15PMEPA1 TGFB1: p-TGFBR:I-SMAD7UBC(457-532) PPP1CB PARD3 SMAD7:NEDD4LUbUBC(153-228) PPP1CA TGFBR2 p-4S,T185,T186-TGFBR1 PRKCZ SMAD7 SMAD7 UBC(533-608) PRKCZ TGFB1:TGFBR2:p-TGFBR1UBC(229-304) PPP1R15A H2OSMAD7:SMURF1:XPO1UBA52(1-76) TGFB1 SMAD7 TGFB1:p-TGFBR:ZFYVE9UBC(229-304) UBC(77-152) SMURF1 PRKCZ MTMR4 TGFB1: TGFBR2:p-TGFBR1: BAMBI:SMAD7TGFB1:p-TGFBR:STRAPRPS27A(1-76) p-S423,S425-SMAD3 UCHL5 TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7p-4S,T185,T186-TGFBR1 UBC(533-608) UBB(77-152) SMURF1 p-2S-SMAD2/3F11R TGFB1 SMURF2UBC(77-152) RHOA SMURF2 RHOA p-S345-PARD6A PiUBB(1-76) ZFYVE9-1 p-S423,S425-SMAD3 UBC(609-684) SMAD7 PARD6A XPO1 TGFB1 UBC(229-304) UBC(229-304) SMAD7:NEDD4LTGFBR2 BAMBI SMURF1 UBC(1-76) p-4S,T185,T186-TGFBR1 CBL UBC(305-380) SMAD2/3:PMEPA1RHOA UBC(457-532) UBC(381-456) SMAD7:SMURF2UBC(305-380) STUB1 UBC(381-456) UBB(153-228) CGN SMAD2 UBC(77-152) XPO1UBC(1-76) UBB(1-76) TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9NEDD8:UBE2MTGFBR2 p-S345-PARD6A p-4S,T185,T186-TGFBR1 TGFBR2 SMAD4FKBP1AUBC(153-228) H2ONEDD4L SMAD3 TGFB1 Dimeric TGFB1TGFBR2:CBLPARD3 MTMR4UBC(381-456) UBA52(1-76) TGFBR2 TGFB1 SMAD7 Ub-SMAD3SMAD3:STUB1K556-TGFBR2-G76-NEDD8 UBC(305-380) Transcriptionalactivity ofSMAD2/SMAD3:SMAD4heterotrimerPiSTUB1SMAD7 UBB(153-228) NEDD4L p-2S-SMAD2/3:MTMR4RPS27A(1-76) TGFBR1 BAMBITGFBR2 p-2S-SMAD2/3:SMAD4p-4S,T185,T186-TGFBR1 F11R UBC(533-608) SMAD2TGFBR2 SMAD2/3TGFB1 Large latent complexof TGFB1TightJunctionComplex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1PRKCZ PPP1CC ZFYVE9-1 ADPFKBP1A CGN RPS27A(1-76) UBC(153-228) FURINSMURF2 UBA52(1-76) PPP1R15A NEDD4L TGFB1 UBB(1-76) SMURF2 PMEPA1 SMAD7 TGFBR1 SMAD7UBB(77-152) p-S423,S425-SMAD3 UBC(1-76) UBB(153-228) TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4LCGN TGFBR1 TGFBR2 TGFBR2 UBC(609-684) SMAD2 PARD3 H2OTGFBR1 p-4S,T185,T186-TGFBR1 TGFBR2 p-4S,T185,T186-TGFBR1 UBC(457-532) C111-UBE2M-G76-NEDD8UBC(1-76) SMAD7UBB(153-228) Pre-TGFB1 complexUBC(229-304) 34, 25, 29, 35, 45...274822228, 9, 49, 51


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. Source:Reactome.

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Bibliography

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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

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ARHGEF18 ProteinQ6ZSZ5 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BAMBI ProteinQ13145 (Uniprot-TrEMBL)
BAMBIProteinQ13145 (Uniprot-TrEMBL)
C111-UBE2M-G76-NEDD8 ProteinQ15843 (Uniprot-TrEMBL)
CBL ProteinP22681 (Uniprot-TrEMBL)
CBLProteinP22681 (Uniprot-TrEMBL)
CGN ProteinQ9P2M7 (Uniprot-TrEMBL)
Dimeric TGFB1:TGFBR2 homodimerComplexR-HSA-170865 (Reactome)
Dimeric TGFB1ComplexR-HSA-170852 (Reactome)
F11R ProteinQ9Y624 (Uniprot-TrEMBL)
FKBP1A ProteinP62942 (Uniprot-TrEMBL)
FKBP1AProteinP62942 (Uniprot-TrEMBL)
FURINProteinP09958 (Uniprot-TrEMBL)
GADD34:PP1ComplexR-HSA-2162158 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
K556-TGFBR2-G76-NEDD8 ProteinQ15843 (Uniprot-TrEMBL)
K567-TGFBR2-G76-NEDD8 ProteinQ15843 (Uniprot-TrEMBL)
Large latent complex of TGFB1ComplexR-HSA-177102 (Reactome)
MTMR4 ProteinQ9NYA4 (Uniprot-TrEMBL)
MTMR4ProteinQ9NYA4 (Uniprot-TrEMBL)
NEDD4L ProteinQ96PU5 (Uniprot-TrEMBL)
NEDD4LProteinQ96PU5 (Uniprot-TrEMBL)
NEDD8-C111-UBE2M ProteinP61081 (Uniprot-TrEMBL)
NEDD8-K556,K567-TGFBR2 ProteinP37173 (Uniprot-TrEMBL)
NEDD8:UBE2MComplexR-HSA-4419896 (Reactome)
Neddylated TGFBR2ComplexR-HSA-4419904 (Reactome)
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 complexComplexR-HSA-171260 (Reactome)
RHOA ProteinP61586 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SMAD2 ProteinQ15796 (Uniprot-TrEMBL)
SMAD2/3:PMEPA1ComplexR-HSA-2187341 (Reactome)
SMAD2/3ProteinR-HSA-171172 (Reactome)
SMAD2:SMURF2ComplexR-HSA-2176457 (Reactome)
SMAD2ProteinQ15796 (Uniprot-TrEMBL)
SMAD3 ProteinP84022 (Uniprot-TrEMBL)
SMAD3:STUB1ComplexR-HSA-2187365 (Reactome)
SMAD3ProteinP84022 (Uniprot-TrEMBL)
SMAD4 ProteinQ13485 (Uniprot-TrEMBL)
SMAD4ProteinQ13485 (Uniprot-TrEMBL)
SMAD7 ProteinO15105 (Uniprot-TrEMBL)
SMAD7:NEDD4LComplexR-HSA-2176418 (Reactome)
SMAD7:NEDD4LComplexR-HSA-2176419 (Reactome)
SMAD7:SMURF/NEDD4LComplexR-HSA-2169026 (Reactome)
SMAD7:SMURF1:XPO1ComplexR-HSA-2167923 (Reactome)
SMAD7:SMURF1ComplexR-HSA-2167913 (Reactome)
SMAD7:SMURF1ComplexR-HSA-2167927 (Reactome)
SMAD7:SMURF2ComplexR-HSA-2167870 (Reactome)
SMAD7:SMURF2ComplexR-HSA-2167883 (Reactome)
SMAD7ProteinO15105 (Uniprot-TrEMBL)
SMURF/NEDD4LProteinR-HSA-2176415 (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 ProteinP01137 (Uniprot-TrEMBL)
TGFB1(30-390) ProteinP01137 (Uniprot-TrEMBL)
TGFB1: TGFBR2:

p-TGFBR1: BAMBI:

SMAD7		ComplexR-HSA-173509 (Reactome)
TGFB1: p-TGFBR: I-SMAD7ComplexR-HSA-173476 (Reactome)
TGFB1: p-TGFBR: STRAP: SMAD7ComplexR-HSA-2128993 (Reactome)
TGFB1:TGFBR2:TGFBR1ComplexR-HSA-170840 (Reactome)
TGFB1:TGFBR2:TGFBR1ComplexR-HSA-2167873 (Reactome)
TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15ComplexR-HSA-2179287 (Reactome)
TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7ComplexR-HSA-2169047 (Reactome)
TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4LComplexR-HSA-2169025 (Reactome)
TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7ComplexR-HSA-2179328 (Reactome)
TGFB1:TGFBR2:p-TGFBR1ComplexR-HSA-170841 (Reactome)
TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9ComplexR-HSA-2167884 (Reactome)
TGFB1:p-TGFBR:STRAPComplexR-HSA-2127564 (Reactome)
TGFB1:p-TGFBR:ZFYVE9:SMAD2/3ComplexR-HSA-171266 (Reactome)
TGFB1:p-TGFBR:ZFYVE9:p-2S-SMAD2/3ComplexR-HSA-171180 (Reactome)
TGFB1:p-TGFBR:ZFYVE9ComplexR-HSA-171173 (Reactome)
TGFBR1 ProteinP36897 (Uniprot-TrEMBL)
TGFBR1:FKBP1AComplexR-HSA-2187279 (Reactome)
TGFBR2 ProteinP37173 (Uniprot-TrEMBL)
TGFBR2:CBLComplexR-HSA-4332229 (Reactome)
TGFBR2ProteinP37173 (Uniprot-TrEMBL)
Tight

Junction

Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOA		ComplexR-HSA-2134522 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1		ComplexR-HSA-2160929 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA		ComplexR-HSA-2134534 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1		ComplexR-HSA-2160934 (Reactome)
Tight

Junction

Complex:TGFBR1:PARD6A:RHOA		ComplexR-HSA-2134509 (Reactome)
Tight Junction Complex:PARD6A:RHOAComplexR-HSA-2134514 (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.
Transcriptional

activity of SMAD2/SMAD3:SMAD4

heterotrimer		PathwayR-HSA-2173793 (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).
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2MProteinP61081 (Uniprot-TrEMBL)
UCHL5 ProteinQ9Y5K5 (Uniprot-TrEMBL)
UCHL5/USP15ProteinR-HSA-2179332 (Reactome)
USP15 ProteinQ9Y4E8 (Uniprot-TrEMBL)
Ub-SMAD2ComplexR-HSA-2176443 (Reactome)
Ub-SMAD3ComplexR-HSA-2187371 (Reactome)
UbProteinR-HSA-113595 (Reactome)
XPO1 ProteinO14980 (Uniprot-TrEMBL)
XPO1ProteinO14980 (Uniprot-TrEMBL)
ZFYVE9-1 ProteinO95405-1 (Uniprot-TrEMBL)
ZFYVE9-1ProteinO95405-1 (Uniprot-TrEMBL)
p-2S-SMAD2/3:MTMR4ComplexR-HSA-2187399 (Reactome)
p-2S-SMAD2/3:PMEPA1ComplexR-HSA-2187343 (Reactome)
p-2S-SMAD2/3:SMAD4ComplexR-HSA-171175 (Reactome)
p-2S-SMAD2/3ProteinR-HSA-171182 (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
ADPArrowR-HSA-170843 (Reactome)
ADPArrowR-HSA-170868 (Reactome)
ADPArrowR-HSA-2134532 (Reactome)
ATPR-HSA-170843 (Reactome)
ATPR-HSA-170868 (Reactome)
ATPR-HSA-2134532 (Reactome)
BAMBIR-HSA-173483 (Reactome)
BAMBImim-catalysisR-HSA-173483 (Reactome)
CBLArrowR-HSA-4332236 (Reactome)
CBLR-HSA-4332235 (Reactome)
Dimeric TGFB1:TGFBR2 homodimerArrowR-HSA-170861 (Reactome)
Dimeric TGFB1:TGFBR2 homodimerR-HSA-170846 (Reactome)
Dimeric TGFB1:TGFBR2 homodimerR-HSA-2134519 (Reactome)
Dimeric TGFB1:TGFBR2 homodimermim-catalysisR-HSA-170846 (Reactome)
Dimeric TGFB1ArrowR-HSA-177107 (Reactome)
Dimeric TGFB1R-HSA-170861 (Reactome)
Dimeric TGFB1mim-catalysisR-HSA-170861 (Reactome)
FKBP1AArrowR-HSA-170846 (Reactome)
FKBP1AArrowR-HSA-2134519 (Reactome)
FURINmim-catalysisR-HSA-170844 (Reactome)
GADD34:PP1ArrowR-HSA-178178 (Reactome)
GADD34:PP1R-HSA-178189 (Reactome)
H2OR-HSA-178178 (Reactome)
H2OR-HSA-2179291 (Reactome)
H2OR-HSA-2187401 (Reactome)
Large latent complex of TGFB1ArrowR-HSA-170844 (Reactome)
Large latent complex of TGFB1R-HSA-177107 (Reactome)
MTMR4ArrowR-HSA-2187401 (Reactome)
MTMR4R-HSA-2187405 (Reactome)
NEDD4LR-HSA-2176416 (Reactome)
NEDD8:UBE2MR-HSA-4332236 (Reactome)
Neddylated TGFBR2ArrowR-HSA-4332236 (Reactome)
PMEPA1R-HSA-2187355 (Reactome)
PMEPA1R-HSA-2187358 (Reactome)
PiArrowR-HSA-178178 (Reactome)
PiArrowR-HSA-2187401 (Reactome)
Pre-TGFB1 complexR-HSA-170844 (Reactome)
R-HSA-170835 (Reactome) The activated TGF-beta receptor complex is internalized by clathrin-mediated endocytosis into early endosomes. ZFYVE9 (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.
R-HSA-170843 (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).
R-HSA-170844 (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)
R-HSA-170846 (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).
R-HSA-170847 (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).
R-HSA-170850 (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 ZFYVE9 (SARA). As a result, the phosphorylated R-SMAD dissociates from the activated receptor complex (TGFBR).
R-HSA-170861 (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).
R-HSA-170868 (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.
R-HSA-173483 (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).
R-HSA-173512 (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.
R-HSA-173542 (Reactome) SMAD2 is polyubiquitinated by SMURF2 and targeted for proteasome-mediated degradation.
R-HSA-177107 (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.
R-HSA-178178 (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.
R-HSA-178189 (Reactome) SMAD7 recruits protein phosphatase 1 (PP1) to TGF-beta receptor complex by binding to the PP1 regulatory subunit PPP1R15A (GADD34). ZFYVE9 (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.
R-HSA-178208 (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).
R-HSA-178215 (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.
R-HSA-178218 (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.
R-HSA-2127562 (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. STRAP is also able to bind unphosphorylated TGF-beta receptor complex, but the physiological significance, if any, of this interaction is not known.
R-HSA-2128994 (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.
R-HSA-2134506 (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.
R-HSA-2134519 (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.
R-HSA-2134532 (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.
R-HSA-2160931 (Reactome) Ubiquitination of RHOA by SMURF1 leads to disassembly of tight junctions, an important step in epithelial to mesenchymal transition.
R-HSA-2160932 (Reactome) SMURF1 ubiquitin ligase is recruited to tight junctions by binding to phosphorylated PARD6A (Ozdamar et al. 2005).
R-HSA-2160935 (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).
R-HSA-2167876 (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.
R-HSA-2167917 (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.
R-HSA-2167924 (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.
R-HSA-2169046 (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.
R-HSA-2169050 (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.
R-HSA-2176416 (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.
R-HSA-2176417 (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.
R-HSA-2176445 (Reactome) SMURF2 binds SMAD2 irrespective of TGF-beta signaling (Zhang et al. 2001).
R-HSA-2176452 (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).
R-HSA-2179291 (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.
R-HSA-2179293 (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.
R-HSA-2187355 (Reactome) PMEPA1 binds phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimers (Watanabe et al. 2010).
R-HSA-2187358 (Reactome) PMEPA1 binds unphosphorylated SMAD2 and SMAD3 and prevents their phosphorylation in response to TGF-beta stimulation (Watanabe et al. 2010).
R-HSA-2187368 (Reactome) STUB1 (CHIP) ubiquitinates SMAD3 in the absence of TGF-beta stimulation (Li et al. 2004, Xin et al. 2005).
R-HSA-2187375 (Reactome) STUB1 (CHIP), an E3 ubiquitin ligase, binds SMAD3 irrespective of TGF-beta stimulation (Li et al. 2004, Xin et al. 2005).
R-HSA-2187382 (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).
R-HSA-2187401 (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).
R-HSA-2187405 (Reactome) A protein phosphatase MTMR4, residing in the early endosome membrane, binds phosphorylated SMAD2 and SMAD3 (Yu et al. 2010).
R-HSA-4332235 (Reactome) The E3 ubiquitin ligase CBL binds the cytoplasmic tail of plasma membrane-bound TGFBR2 (TGF-beta receptor 2) but not TGFBR1 (TGF-beta receptor 1). The tyrosine kinase binding (TKB) domain of CBL is involved in this interaction (Zuo et al. 2013).
R-HSA-4332236 (Reactome) CBL neddylates TGFBR2 on lysine residues K556 and K567. The E3 ubiquitin ligase activity of CBL is necessary for this modification, and the kinase activity of TGFBR2 is also required. CBL-mediated neddylation prolongs the half-life of TGFBR2, thereby enhancing signaling by the TGF-beta receptor complex. CBLB, a CBL-related protein, may cooperate with CBL in TGFBR2 neddylation (Zuo et al. 2013).
SMAD2/3:PMEPA1ArrowR-HSA-2187358 (Reactome)
SMAD2/3ArrowR-HSA-2187401 (Reactome)
SMAD2/3R-HSA-170835 (Reactome)
SMAD2/3R-HSA-2187358 (Reactome)
SMAD2:SMURF2ArrowR-HSA-2176445 (Reactome)
SMAD2:SMURF2R-HSA-173542 (Reactome)
SMAD2:SMURF2mim-catalysisR-HSA-173542 (Reactome)
SMAD2R-HSA-2176445 (Reactome)
SMAD3:STUB1ArrowR-HSA-2187375 (Reactome)
SMAD3:STUB1R-HSA-2187368 (Reactome)
SMAD3:STUB1mim-catalysisR-HSA-2187368 (Reactome)
SMAD3R-HSA-2187375 (Reactome)
SMAD4R-HSA-170847 (Reactome)
SMAD7:NEDD4LArrowR-HSA-2176416 (Reactome)
SMAD7:NEDD4LArrowR-HSA-2176417 (Reactome)
SMAD7:NEDD4LR-HSA-2176417 (Reactome)
SMAD7:SMURF/NEDD4LR-HSA-178218 (Reactome)
SMAD7:SMURF1:XPO1ArrowR-HSA-2167924 (Reactome)
SMAD7:SMURF1:XPO1R-HSA-178215 (Reactome)
SMAD7:SMURF1:XPO1mim-catalysisR-HSA-178215 (Reactome)
SMAD7:SMURF1ArrowR-HSA-178215 (Reactome)
SMAD7:SMURF1ArrowR-HSA-2167917 (Reactome)
SMAD7:SMURF1R-HSA-2167924 (Reactome)
SMAD7:SMURF2ArrowR-HSA-178208 (Reactome)
SMAD7:SMURF2ArrowR-HSA-2167876 (Reactome)
SMAD7:SMURF2R-HSA-2167876 (Reactome)
SMAD7ArrowR-HSA-178178 (Reactome)
SMAD7R-HSA-173483 (Reactome)
SMAD7R-HSA-173512 (Reactome)
SMAD7R-HSA-178208 (Reactome)
SMAD7R-HSA-2128994 (Reactome)
SMAD7R-HSA-2167917 (Reactome)
SMAD7R-HSA-2176416 (Reactome)
SMURF/NEDD4LArrowR-HSA-2169050 (Reactome)
SMURF1R-HSA-2160932 (Reactome)
SMURF1R-HSA-2167917 (Reactome)
SMURF2ArrowR-HSA-173542 (Reactome)
SMURF2R-HSA-178208 (Reactome)
SMURF2R-HSA-2176445 (Reactome)
STRAPR-HSA-2127562 (Reactome)
STUB1ArrowR-HSA-2187368 (Reactome)
STUB1R-HSA-2187375 (Reactome)
TGFB1: TGFBR2:

p-TGFBR1: BAMBI:

SMAD7		ArrowR-HSA-173483 (Reactome)
TGFB1: p-TGFBR: I-SMAD7ArrowR-HSA-173512 (Reactome)
TGFB1: p-TGFBR: I-SMAD7R-HSA-178189 (Reactome)
TGFB1: p-TGFBR: STRAP: SMAD7ArrowR-HSA-2128994 (Reactome)
TGFB1:TGFBR2:TGFBR1ArrowR-HSA-170846 (Reactome)
TGFB1:TGFBR2:TGFBR1ArrowR-HSA-178178 (Reactome)
TGFB1:TGFBR2:TGFBR1R-HSA-170843 (Reactome)
TGFB1:TGFBR2:TGFBR1mim-catalysisR-HSA-170843 (Reactome)
TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15ArrowR-HSA-2179293 (Reactome)
TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15R-HSA-2179291 (Reactome)
TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15mim-catalysisR-HSA-2179291 (Reactome)
TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7ArrowR-HSA-2169050 (Reactome)
TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7R-HSA-2169046 (Reactome)
TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7R-HSA-2179293 (Reactome)
TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4LArrowR-HSA-178218 (Reactome)
TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4LR-HSA-2169050 (Reactome)
TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4Lmim-catalysisR-HSA-2169050 (Reactome)
TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7ArrowR-HSA-2179291 (Reactome)
TGFB1:TGFBR2:p-TGFBR1ArrowR-HSA-170843 (Reactome)
TGFB1:TGFBR2:p-TGFBR1R-HSA-170835 (Reactome)
TGFB1:TGFBR2:p-TGFBR1R-HSA-173483 (Reactome)
TGFB1:TGFBR2:p-TGFBR1R-HSA-173512 (Reactome)
TGFB1:TGFBR2:p-TGFBR1R-HSA-178218 (Reactome)
TGFB1:TGFBR2:p-TGFBR1R-HSA-2127562 (Reactome)
TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9ArrowR-HSA-178189 (Reactome)
TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9R-HSA-178178 (Reactome)
TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9mim-catalysisR-HSA-178178 (Reactome)
TGFB1:p-TGFBR:STRAPArrowR-HSA-2127562 (Reactome)
TGFB1:p-TGFBR:STRAPR-HSA-2128994 (Reactome)
TGFB1:p-TGFBR:ZFYVE9:SMAD2/3ArrowR-HSA-170835 (Reactome)
TGFB1:p-TGFBR:ZFYVE9:SMAD2/3R-HSA-170868 (Reactome)
TGFB1:p-TGFBR:ZFYVE9:SMAD2/3mim-catalysisR-HSA-170868 (Reactome)
TGFB1:p-TGFBR:ZFYVE9:p-2S-SMAD2/3ArrowR-HSA-170868 (Reactome)
TGFB1:p-TGFBR:ZFYVE9:p-2S-SMAD2/3R-HSA-170850 (Reactome)
TGFB1:p-TGFBR:ZFYVE9ArrowR-HSA-170850 (Reactome)
TGFBR1:FKBP1AR-HSA-170846 (Reactome)
TGFBR1:FKBP1AR-HSA-2134506 (Reactome)
TGFBR2:CBLArrowR-HSA-4332235 (Reactome)
TGFBR2:CBLR-HSA-4332236 (Reactome)
TGFBR2:CBLmim-catalysisR-HSA-4332236 (Reactome)
TGFBR2R-HSA-170861 (Reactome)
TGFBR2R-HSA-4332235 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOA		ArrowR-HSA-2134519 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOA		R-HSA-2134532 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1		ArrowR-HSA-2160932 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1		R-HSA-2160935 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA		ArrowR-HSA-2134532 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA		R-HSA-2160932 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1		ArrowR-HSA-2160935 (Reactome)
Tight

Junction

Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1		R-HSA-2160931 (Reactome)
Tight

Junction

Complex:TGFBR1:PARD6A:RHOA		ArrowR-HSA-2134506 (Reactome)
Tight

Junction

Complex:TGFBR1:PARD6A:RHOA		R-HSA-2134519 (Reactome)
Tight Junction Complex:PARD6A:RHOAR-HSA-2134506 (Reactome)
UBE2MArrowR-HSA-4332236 (Reactome)
UCHL5/USP15ArrowR-HSA-2179291 (Reactome)
UCHL5/USP15R-HSA-2179293 (Reactome)
Ub-SMAD2ArrowR-HSA-173542 (Reactome)
Ub-SMAD2R-HSA-2176452 (Reactome)
Ub-SMAD3ArrowR-HSA-2187368 (Reactome)
Ub-SMAD3R-HSA-2187382 (Reactome)
UbArrowR-HSA-2179291 (Reactome)
UbR-HSA-173542 (Reactome)
UbR-HSA-2160935 (Reactome)
UbR-HSA-2169050 (Reactome)
UbR-HSA-2187368 (Reactome)
XPO1ArrowR-HSA-178215 (Reactome)
XPO1R-HSA-2167924 (Reactome)
ZFYVE9-1ArrowR-HSA-178178 (Reactome)
ZFYVE9-1R-HSA-170835 (Reactome)
ZFYVE9-1R-HSA-178189 (Reactome)
ZFYVE9-1mim-catalysisR-HSA-170835 (Reactome)
p-2S-SMAD2/3:MTMR4ArrowR-HSA-2187405 (Reactome)
p-2S-SMAD2/3:MTMR4R-HSA-2187401 (Reactome)
p-2S-SMAD2/3:MTMR4mim-catalysisR-HSA-2187401 (Reactome)
p-2S-SMAD2/3:PMEPA1ArrowR-HSA-2187355 (Reactome)
p-2S-SMAD2/3:SMAD4ArrowR-HSA-170847 (Reactome)
p-2S-SMAD2/3ArrowR-HSA-170850 (Reactome)
p-2S-SMAD2/3R-HSA-170847 (Reactome)
p-2S-SMAD2/3R-HSA-2187355 (Reactome)
p-2S-SMAD2/3R-HSA-2187405 (Reactome)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP2742"
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