Signaling by TGF-beta receptor complex (Homo sapiens)
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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
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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- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J.; ''Mechanism of activation of the TGF-beta receptor.''; PubMed Europe PMC Scholia
- 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
- 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
- Kang JS, Liu C, Derynck R.; ''New regulatory mechanisms of TGF-beta receptor function.''; PubMed Europe PMC Scholia
- 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
- 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
- Datta PK, Moses HL.; ''STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling.''; PubMed Europe PMC Scholia
- 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
- 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
- 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
- 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
- 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
- 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
- Chen YG, Liu F, Massague J.; ''Mechanism of TGFbeta receptor inhibition by FKBP12.''; PubMed Europe PMC Scholia
- 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
- Annes JP, Munger JS, Rifkin DB.; ''Making sense of latent TGFbeta activation.''; PubMed Europe PMC Scholia
- 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
- 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
- Gong L, Yeh ET.; ''Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway.''; PubMed Europe PMC Scholia
- 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
- Wotton D, Lo RS, Lee S, Massagué J.; ''A Smad transcriptional corepressor.''; PubMed Europe PMC Scholia
- 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
- 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
- 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
- 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
- Keski-Oja J, Koli K, von Melchner H.; ''TGF-beta activation by traction?''; PubMed Europe PMC Scholia
- 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
- 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
- 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
- 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
- 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
- Souchelnytskyi S, Rönnstrand L, Heldin CH, ten Dijke P.; ''Phosphorylation of Smad signaling proteins by receptor serine/threonine kinases.''; PubMed Europe PMC Scholia
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
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External references
DataNodes
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| Name | Type | Database reference | Comment |
|---|---|---|---|
| ADP | Metabolite | CHEBI:16761 (ChEBI)  | |
| ARHGEF18 [cell junction] | Protein | Q6ZSZ5 (Uniprot-TrEMBL) | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| BAMBI [plasma membrane] | Protein | Q13145 (Uniprot-TrEMBL) | |
| BAMBI | Protein | Q13145 (Uniprot-TrEMBL) | |
| CGN [cell junction] | Protein | Q9P2M7 (Uniprot-TrEMBL) | |
| Dimeric TGFB1:TGFBR2 homodimer | Complex | REACT_7218 (Reactome) | |
| Dimeric TGFB1 | Complex | REACT_6996 (Reactome) | |
| F11R [cell junction] | Protein | Q9Y624 (Uniprot-TrEMBL) | |
| FKBP1A [cytosol] | Protein | P62942 (Uniprot-TrEMBL) | |
| FKBP1A | Protein | P62942 (Uniprot-TrEMBL) | |
| FURIN | Protein | P09958 (Uniprot-TrEMBL) | |
| GADD34:PP1 | Complex | REACT_124291 (Reactome) | |
| H2O | Metabolite | CHEBI:15377 (ChEBI) | |
| Large latent complex of TGFB1 | Complex | REACT_7797 (Reactome) | |
| MTMR4 [early endosome membrane] | Protein | Q9NYA4 (Uniprot-TrEMBL) | |
| MTMR4 | Protein | Q9NYA4 (Uniprot-TrEMBL) | |
| NEDD4L(2-975) [cytosol] | Protein | Q96PU5 (Uniprot-TrEMBL) | |
| NEDD4L(2-975) [nucleoplasm] | Protein | Q96PU5 (Uniprot-TrEMBL) | |
| NEDD4L(2-975) | Protein | Q96PU5 (Uniprot-TrEMBL) | |
| PARD3 [cell junction] | Protein | Q8TEW0 (Uniprot-TrEMBL) | |
| PARD6A [cell junction] | Protein | Q9NPB6 (Uniprot-TrEMBL) | |
| PMEPA1 [early endosome membrane] | Protein | Q969W9 (Uniprot-TrEMBL) | |
| PMEPA1 [plasma membrane] | Protein | Q969W9 (Uniprot-TrEMBL) | |
| PMEPA1 | Protein | Q969W9 (Uniprot-TrEMBL) | |
| PPP1CA [cytosol] | Protein | P62136 (Uniprot-TrEMBL) | |
| PPP1CB [cytosol] | Protein | P62140 (Uniprot-TrEMBL) | |
| PPP1CC [cytosol] | Protein | P36873 (Uniprot-TrEMBL) | |
| PPP1R15A [cytosol] | Protein | O75807 (Uniprot-TrEMBL) | |
| PRKCZ [cell junction] | Protein | Q05513 (Uniprot-TrEMBL) | |
| Pi | Metabolite | CHEBI:18367 (ChEBI) | |
| Pre-TGFB1 complex | Complex | REACT_7332 (Reactome) | |
| RHOA [cell junction] | Protein | P61586 (Uniprot-TrEMBL) | |
| RPS27A(1-76) [cytosol] | Protein | P62979 (Uniprot-TrEMBL) | |
| SMAD2 [cytosol] | Protein | Q15796 (Uniprot-TrEMBL) | |
| SMAD2/3:PMEPA1 | Complex | REACT_121843 (Reactome) | |
| SMAD2/3 | Protein | REACT_7451 (Reactome) | |
| SMAD2:SMURF2 | Complex | REACT_122626 (Reactome) | |
| SMAD2 | Protein | Q15796 (Uniprot-TrEMBL) | |
| SMAD3 [cytosol] | Protein | P84022 (Uniprot-TrEMBL) | |
| SMAD3:STUB1 | Complex | REACT_124835 (Reactome) | |
| SMAD3 | Protein | P84022 (Uniprot-TrEMBL) | |
| SMAD4 [cytosol] | Protein | Q13485 (Uniprot-TrEMBL) | |
| SMAD4 | Protein | Q13485 (Uniprot-TrEMBL) | |
| SMAD7 [cytosol] | Protein | O15105 (Uniprot-TrEMBL) | |
| SMAD7 [nucleoplasm] | Protein | O15105 (Uniprot-TrEMBL) | |
| SMAD7:NEDD4L | Complex | REACT_124391 (Reactome) | |
| SMAD7:NEDD4L | Complex | REACT_125398 (Reactome) | |
| SMAD7:SMURF/NEDD4L | Complex | REACT_123020 (Reactome) | |
| SMAD7:SMURF1:XPO1 | Complex | REACT_122262 (Reactome) | |
| SMAD7:SMURF1 | Complex | REACT_122445 (Reactome) | |
| SMAD7:SMURF1 | Complex | REACT_124389 (Reactome) | |
| SMAD7:SMURF2 | Complex | REACT_121453 (Reactome) | |
| SMAD7:SMURF2 | Complex | REACT_124286 (Reactome) | |
| SMAD7 | Protein | O15105 (Uniprot-TrEMBL) | |
| SMURF/NEDD4L | Protein | REACT_124598 (Reactome) | |
| SMURF1 [cytosol] | Protein | Q9HCE7 (Uniprot-TrEMBL) | |
| SMURF1 [nucleoplasm] | Protein | Q9HCE7 (Uniprot-TrEMBL) | |
| SMURF1 | Protein | Q9HCE7 (Uniprot-TrEMBL) | |
| SMURF2 [cytosol] | Protein | Q9HAU4 (Uniprot-TrEMBL) | |
| SMURF2 [nucleoplasm] | Protein | Q9HAU4 (Uniprot-TrEMBL) | |
| SMURF2 | Protein | Q9HAU4 (Uniprot-TrEMBL) | |
| STRAP [cytosol] | Protein | Q9Y3F4 (Uniprot-TrEMBL) | |
| STRAP | Protein | Q9Y3F4 (Uniprot-TrEMBL) | |
| STUB1 [cytosol] | Protein | Q9UNE7 (Uniprot-TrEMBL) | |
| STUB1 | Protein | Q9UNE7 (Uniprot-TrEMBL) | |
| TGFB1(279-390) [Golgi lumen] | Protein | P01137 (Uniprot-TrEMBL) | |
| TGFB1(279-390)
[extracellular region] | Protein | P01137 (Uniprot-TrEMBL) | |
| TGFB1(30-390) [Golgi lumen] | Protein | P01137 (Uniprot-TrEMBL) | |
| TGFB1: TGFBR2:
p-TGFBR1: BAMBI: SMAD7 | Complex | REACT_161164 (Reactome) | |
| TGFB1: p-TGFBR: I-SMAD7 | Complex | REACT_7842 (Reactome) | |
| TGFB1: p-TGFBR: STRAP: SMAD7 | Complex | REACT_122595 (Reactome) | |
| TGFB1:TGFBR2:TGFBR1 | Complex | REACT_125329 (Reactome) | |
| TGFB1:TGFBR2:TGFBR1 | Complex | REACT_7425 (Reactome) | |
| TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15 | Complex | REACT_124446 (Reactome) | |
| TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7 | Complex | REACT_125417 (Reactome) | |
| TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4L | Complex | REACT_123560 (Reactome) | |
| TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7 | Complex | REACT_122134 (Reactome) | |
| TGFB1:TGFBR2:p-TGFBR1 | Complex | REACT_7428 (Reactome) | |
| TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:SARA | Complex | REACT_122135 (Reactome) | |
| TGFB1:p-TGFBR:SARA:SMAD2/3 | Complex | REACT_7757 (Reactome) | |
| TGFB1:p-TGFBR:SARA:p-2S-SMAD2/3 | Complex | REACT_6989 (Reactome) | |
| TGFB1:p-TGFBR:SARA | Complex | REACT_7772 (Reactome) | |
| TGFB1:p-TGFBR:STRAP | Complex | REACT_125338 (Reactome) | |
| TGFBR1 [plasma membrane] | Protein | P36897 (Uniprot-TrEMBL) | |
| TGFBR1:FKBP1A | Complex | REACT_122814 (Reactome) | |
| TGFBR2 [plasma membrane] | Protein | P37173 (Uniprot-TrEMBL) | |
| TGFBR2 | Protein | P37173 (Uniprot-TrEMBL) | |
| TGFBR:STRAP | Complex | REACT_122598 (Reactome) | |
| Tight Junction Complex:PARD6A:RHOA | Complex | REACT_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 | Complex | REACT_122365 (Reactome) | |
| Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1 | Complex | REACT_121985 (Reactome) | |
| Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA | Complex | REACT_124952 (Reactome) | |
| Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1 | Complex | REACT_122343 (Reactome) | |
| Tight Junction Complex:TGFBR1:PARD6A:RHOA | Complex | REACT_124021 (Reactome) | |
| Transcriptional
activity of SMAD2/SMAD3:SMAD4 heterotrimer | Pathway | WP2755 (WikiPathways) | 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) [cytosol] | Protein | P62987 (Uniprot-TrEMBL) | |
| UBB(1-76) [cytosol] | Protein | P0CG47 (Uniprot-TrEMBL) | |
| UBB(153-228) [cytosol] | Protein | P0CG47 (Uniprot-TrEMBL) | |
| UBB(77-152) [cytosol] | Protein | P0CG47 (Uniprot-TrEMBL) | |
| UBC(1-76) [cytosol] | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(153-228) [cytosol] | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(229-304) [cytosol] | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(305-380) [cytosol] | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(381-456) [cytosol] | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(457-532) [cytosol] | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(533-608) [cytosol] | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(609-684) [cytosol] | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UBC(77-152) [cytosol] | Protein | P0CG48 (Uniprot-TrEMBL) | |
| UCHL5 [cytosol] | Protein | Q9Y5K5 (Uniprot-TrEMBL) | |
| UCHL5/USP15 | Protein | REACT_122261 (Reactome) | |
| USP15 [cytosol] | Protein | Q9Y4E8 (Uniprot-TrEMBL) | |
| Ub-SMAD2 | Complex | REACT_121470 (Reactome) | |
| Ub-SMAD3 | Complex | REACT_123646 (Reactome) | |
| Ub | Protein | REACT_3316 (Reactome) | |
| XPO1 [nucleoplasm] | Protein | O14980 (Uniprot-TrEMBL) | |
| XPO1 | Protein | O14980 (Uniprot-TrEMBL) | |
| ZFYVE9-1 [early endosome membrane] | Protein | O95405-1 (Uniprot-TrEMBL) | |
| ZFYVE9-1 | Protein | O95405-1 (Uniprot-TrEMBL) | |
| p-2S-SMAD2/3:MTMR4 | Complex | REACT_123224 (Reactome) | |
| p-2S-SMAD2/3:PMEPA1 | Complex | REACT_122643 (Reactome) | |
| p-2S-SMAD2/3:SMAD4 | Complex | REACT_7344 (Reactome) | |
| p-2S-SMAD2/3 | Protein | REACT_7364 (Reactome) | |
| p-4S,T185,T186-TGFBR1 [plasma membrane] | Protein | P36897 (Uniprot-TrEMBL) | |
| p-S345-PARD6A [plasma membrane] | Protein | Q9NPB6 (Uniprot-TrEMBL) | |
| p-S423,S425-SMAD3 [cytosol] | Protein | P84022 (Uniprot-TrEMBL) | |
| p-S465,S467-SMAD2 [cytosol] | Protein | Q15796 (Uniprot-TrEMBL) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADP | Arrow | REACT_121038 (Reactome) | ||
| ADP | Arrow | REACT_6816 (Reactome) | ||
| ADP | Arrow | REACT_6879 (Reactome) | ||
| ATP | REACT_121038 (Reactome) | |||
| ATP | REACT_6816 (Reactome) | |||
| ATP | REACT_6879 (Reactome) | |||
| BAMBI | REACT_160299 (Reactome) | |||
| BAMBI | mim-catalysis | REACT_160299 (Reactome) | ||
| Dimeric TGFB1:TGFBR2 homodimer | Arrow | REACT_6872 (Reactome) | ||
| Dimeric TGFB1:TGFBR2 homodimer | REACT_121305 (Reactome) | |||
| Dimeric TGFB1:TGFBR2 homodimer | REACT_6945 (Reactome) | |||
| Dimeric TGFB1:TGFBR2 homodimer | mim-catalysis | REACT_6945 (Reactome) | ||
| Dimeric TGFB1 | Arrow | REACT_6888 (Reactome) | ||
| Dimeric TGFB1 | REACT_6872 (Reactome) | |||
| Dimeric TGFB1 | mim-catalysis | REACT_6872 (Reactome) | ||
| FKBP1A | Arrow | REACT_121305 (Reactome) | ||
| FKBP1A | Arrow | REACT_6945 (Reactome) | ||
| FURIN | mim-catalysis | REACT_6931 (Reactome) | ||
| GADD34:PP1 | Arrow | REACT_121355 (Reactome) | ||
| GADD34:PP1 | REACT_121211 (Reactome) | |||
| H2O | REACT_120908 (Reactome) | |||
| H2O | REACT_120959 (Reactome) | |||
| H2O | REACT_121355 (Reactome) | |||
| Large latent complex of TGFB1 | Arrow | REACT_6931 (Reactome) | ||
| Large latent complex of TGFB1 | REACT_6888 (Reactome) | |||
| MTMR4 | Arrow | REACT_120908 (Reactome) | ||
| MTMR4 | REACT_120991 (Reactome) | |||
| NEDD4L(2-975) | REACT_121293 (Reactome) | |||
| PMEPA1 | REACT_120812 (Reactome) | |||
| PMEPA1 | REACT_121239 (Reactome) | |||
| Pi | Arrow | REACT_120908 (Reactome) | ||
| Pi | Arrow | REACT_121355 (Reactome) | ||
| Pre-TGFB1 complex | REACT_6931 (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). | |||
| SMAD2/3:PMEPA1 | Arrow | REACT_121239 (Reactome) | ||
| SMAD2/3 | Arrow | REACT_120908 (Reactome) | ||
| SMAD2/3 | REACT_121239 (Reactome) | |||
| SMAD2/3 | REACT_6923 (Reactome) | |||
| SMAD2:SMURF2 | Arrow | REACT_121290 (Reactome) | ||
| SMAD2:SMURF2 | REACT_6786 (Reactome) | |||
| SMAD2:SMURF2 | mim-catalysis | REACT_6786 (Reactome) | ||
| SMAD2 | REACT_121290 (Reactome) | |||
| SMAD3:STUB1 | Arrow | REACT_120728 (Reactome) | ||
| SMAD3:STUB1 | REACT_120732 (Reactome) | |||
| SMAD3:STUB1 | mim-catalysis | REACT_120732 (Reactome) | ||
| SMAD3 | REACT_120728 (Reactome) | |||
| SMAD4 | REACT_6760 (Reactome) | |||
| SMAD7:NEDD4L | Arrow | REACT_120817 (Reactome) | ||
| SMAD7:NEDD4L | Arrow | REACT_121293 (Reactome) | ||
| SMAD7:NEDD4L | REACT_120817 (Reactome) | |||
| SMAD7:SMURF/NEDD4L | REACT_121080 (Reactome) | |||
| SMAD7:SMURF1:XPO1 | Arrow | REACT_121148 (Reactome) | ||
| SMAD7:SMURF1:XPO1 | REACT_120910 (Reactome) | |||
| SMAD7:SMURF1:XPO1 | mim-catalysis | REACT_120910 (Reactome) | ||
| SMAD7:SMURF1 | Arrow | REACT_120910 (Reactome) | ||
| SMAD7:SMURF1 | Arrow | REACT_121065 (Reactome) | ||
| SMAD7:SMURF1 | REACT_121148 (Reactome) | |||
| SMAD7:SMURF2 | Arrow | REACT_120957 (Reactome) | ||
| SMAD7:SMURF2 | Arrow | REACT_121124 (Reactome) | ||
| SMAD7:SMURF2 | REACT_120957 (Reactome) | |||
| SMAD7 | Arrow | REACT_121355 (Reactome) | ||
| SMAD7 | REACT_121065 (Reactome) | |||
| SMAD7 | REACT_121124 (Reactome) | |||
| SMAD7 | REACT_121293 (Reactome) | |||
| SMAD7 | REACT_121338 (Reactome) | |||
| SMAD7 | REACT_160299 (Reactome) | |||
| SMAD7 | REACT_6909 (Reactome) | |||
| SMURF/NEDD4L | Arrow | REACT_121128 (Reactome) | ||
| SMURF1 | REACT_121065 (Reactome) | |||
| SMURF1 | REACT_121150 (Reactome) | |||
| SMURF2 | Arrow | REACT_6786 (Reactome) | ||
| SMURF2 | REACT_121124 (Reactome) | |||
| SMURF2 | REACT_121290 (Reactome) | |||
| STRAP | REACT_120784 (Reactome) | |||
| STRAP | REACT_120862 (Reactome) | |||
| STUB1 | Arrow | REACT_120732 (Reactome) | ||
| STUB1 | REACT_120728 (Reactome) | |||
| TGFB1: TGFBR2:
p-TGFBR1: BAMBI: SMAD7 | Arrow | REACT_160299 (Reactome) | ||
| TGFB1: p-TGFBR: I-SMAD7 | Arrow | REACT_6909 (Reactome) | ||
| TGFB1: p-TGFBR: I-SMAD7 | REACT_121211 (Reactome) | |||
| TGFB1: p-TGFBR: STRAP: SMAD7 | Arrow | REACT_121338 (Reactome) | ||
| TGFB1:TGFBR2:TGFBR1 | Arrow | REACT_121355 (Reactome) | ||
| TGFB1:TGFBR2:TGFBR1 | Arrow | REACT_6945 (Reactome) | ||
| TGFB1:TGFBR2:TGFBR1 | REACT_120784 (Reactome) | |||
| TGFB1:TGFBR2:TGFBR1 | REACT_6816 (Reactome) | |||
| TGFB1:TGFBR2:TGFBR1 | mim-catalysis | REACT_6816 (Reactome) | ||
| TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15 | Arrow | REACT_120979 (Reactome) | ||
| TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15 | REACT_120959 (Reactome) | |||
| TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15 | mim-catalysis | REACT_120959 (Reactome) | ||
| TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7 | Arrow | REACT_121128 (Reactome) | ||
| TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7 | REACT_120808 (Reactome) | |||
| TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7 | REACT_120979 (Reactome) | |||
| TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4L | Arrow | REACT_121080 (Reactome) | ||
| TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4L | REACT_121128 (Reactome) | |||
| TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4L | mim-catalysis | REACT_121128 (Reactome) | ||
| TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7 | Arrow | REACT_120959 (Reactome) | ||
| TGFB1:TGFBR2:p-TGFBR1 | Arrow | REACT_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 | Arrow | REACT_121211 (Reactome) | ||
| TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:SARA | REACT_121355 (Reactome) | |||
| TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:SARA | mim-catalysis | REACT_121355 (Reactome) | ||
| TGFB1:p-TGFBR:SARA:SMAD2/3 | Arrow | REACT_6923 (Reactome) | ||
| TGFB1:p-TGFBR:SARA:SMAD2/3 | REACT_6879 (Reactome) | |||
| TGFB1:p-TGFBR:SARA:SMAD2/3 | mim-catalysis | REACT_6879 (Reactome) | ||
| TGFB1:p-TGFBR:SARA:p-2S-SMAD2/3 | Arrow | REACT_6879 (Reactome) | ||
| TGFB1:p-TGFBR:SARA:p-2S-SMAD2/3 | REACT_6744 (Reactome) | |||
| TGFB1:p-TGFBR:SARA | Arrow | REACT_6744 (Reactome) | ||
| TGFB1:p-TGFBR:STRAP | Arrow | REACT_120862 (Reactome) | ||
| TGFB1:p-TGFBR:STRAP | REACT_121338 (Reactome) | |||
| TGFBR1:FKBP1A | REACT_121029 (Reactome) | |||
| TGFBR1:FKBP1A | REACT_6945 (Reactome) | |||
| TGFBR2 | REACT_6872 (Reactome) | |||
| TGFBR:STRAP | Arrow | REACT_120784 (Reactome) | ||
| Tight Junction Complex:PARD6A:RHOA | REACT_121029 (Reactome) | |||
| Tight Junction Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOA | Arrow | REACT_121305 (Reactome) | ||
| Tight Junction Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOA | REACT_121038 (Reactome) | |||
| Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1 | Arrow | REACT_121150 (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 | Arrow | REACT_121038 (Reactome) | ||
| Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA | REACT_121150 (Reactome) | |||
| Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1 | Arrow | REACT_121146 (Reactome) | ||
| Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1 | REACT_120890 (Reactome) | |||
| Tight Junction Complex:TGFBR1:PARD6A:RHOA | Arrow | REACT_121029 (Reactome) | ||
| Tight Junction Complex:TGFBR1:PARD6A:RHOA | REACT_121305 (Reactome) | |||
| UCHL5/USP15 | Arrow | REACT_120959 (Reactome) | ||
| UCHL5/USP15 | REACT_120979 (Reactome) | |||
| Ub-SMAD2 | Arrow | REACT_6786 (Reactome) | ||
| Ub-SMAD2 | REACT_121119 (Reactome) | |||
| Ub-SMAD3 | Arrow | REACT_120732 (Reactome) | ||
| Ub-SMAD3 | REACT_121055 (Reactome) | |||
| Ub | Arrow | REACT_120959 (Reactome) | ||
| Ub | REACT_120732 (Reactome) | |||
| Ub | REACT_121128 (Reactome) | |||
| Ub | REACT_121146 (Reactome) | |||
| Ub | REACT_6786 (Reactome) | |||
| XPO1 | Arrow | REACT_120910 (Reactome) | ||
| XPO1 | REACT_121148 (Reactome) | |||
| ZFYVE9-1 | Arrow | REACT_121355 (Reactome) | ||
| ZFYVE9-1 | REACT_121211 (Reactome) | |||
| ZFYVE9-1 | REACT_6923 (Reactome) | |||
| ZFYVE9-1 | mim-catalysis | REACT_6923 (Reactome) | ||
| p-2S-SMAD2/3:MTMR4 | Arrow | REACT_120991 (Reactome) | ||
| p-2S-SMAD2/3:MTMR4 | REACT_120908 (Reactome) | |||
| p-2S-SMAD2/3:MTMR4 | mim-catalysis | REACT_120908 (Reactome) | ||
| p-2S-SMAD2/3:PMEPA1 | Arrow | REACT_120812 (Reactome) | ||
| p-2S-SMAD2/3:SMAD4 | Arrow | REACT_6760 (Reactome) | ||
| p-2S-SMAD2/3 | Arrow | REACT_6744 (Reactome) | ||
| p-2S-SMAD2/3 | REACT_120812 (Reactome) | |||
| p-2S-SMAD2/3 | REACT_120991 (Reactome) | |||
| p-2S-SMAD2/3 | REACT_6760 (Reactome) |
