BioPAX pathway converted from "PP1 dephosphorylates TGFBR1" in the Reactome database. 3.1.3.16 PP1 dephosphorylates TGFBR1 PP1 dephosphorylates TGFBR1 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. Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Reviewed: Huang, Tao, 2012-05-14 Edited: Jassal, B, 2012-04-10 Reactome DB_ID: 2167884 1 early endosome membrane GO 0031901 TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9 [early endosome membrane] TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:ZFYVE9 TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:SARA Reactome DB_ID: 173476 1 plasma membrane GO 0005886 TGFB1: p-TGFBR: I-SMAD7 [plasma membrane] TGFB1: p-TGFBR: I-SMAD7 TGFB1:TGFBR2:p-5S-T185-TGFBR1:I-SMAD7 TGF-beta 1:type II receptor:Phospho-type I receptor:I-SMAD7 complex Reactome DB_ID: 173478 1 cytosol GO 0005829 UniProt:O15105 SMAD7 SMAD7 MADH7 MADH8 SMAD7 FUNCTION Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Interacts with WWP1 (By similarity). Interacts with COPS5. Interacts with NEDD4L. Interacts with STAMBP. Interacts with RNF111, AXIN1 and AXIN2. Interacts with PPP1R15A. Interacts (via MH2 domain) with EP300. Interacts with ACVR1B, SMURF1, SMURF2 and TGFBR1; SMAD7 recruits SMURF1 and SMURF2 to the TGF-beta receptor and regulates its degradation. Interacts with PDPK1 (via PH domain).TISSUE SPECIFICITY Ubiquitous with higher expression in the lung and vascular endothelium.INDUCTION By TGFB1.PTM Phosphorylation on Ser-249 does not affect its stability, nuclear localization or inhibitory function in TGFB signaling; however it affects its ability to regulate transcription (By similarity). Phosphorylated by PDPK1.PTM Ubiquitinated by WWP1 (By similarity). Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation (PubMed:14657019, PubMed:16601693). In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation (PubMed:11278251).PTM Acetylation prevents ubiquitination and degradation mediated by SMURF1.SIMILARITY Belongs to the dwarfin/SMAD family. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt O15105 Chain Coordinates 1 EQUAL 426 EQUAL Reactome DB_ID: 170841 1 TGFB1:TGFBR2:p-TGFBR1 [plasma membrane] TGFB1:TGFBR2:p-TGFBR1 TGF-beta 1:type II receptor:Phospho-type I receptor complex Reactome DB_ID: 170863 1 p-TGFBR1 [plasma membrane] p-TGFBR1 Phospho-TGF-beta I receptor complex Reactome DB_ID: 170849 2 UniProt:P36897 TGFBR1 TGFBR1 ALK5 SKR4 TGFBR1 FUNCTION Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.ACTIVITY REGULATION Kept in an inactive conformation by FKBP1A preventing receptor activation in absence of ligand. CD109 is another inhibitor of the receptor.SUBUNIT Homodimer; in the endoplasmic reticulum but also at the cell membrane. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGBRB1 and TGFBR2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Interacts with CD109; inhibits TGF-beta receptor activation in keratinocytes. Interacts with RBPMS. Interacts (unphosphorylated) with FKBP1A; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation. Interacts with SMAD2, SMAD3 and ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with TRAF6 and MAP3K7; induces MAP3K7 activation by TRAF6. Interacts with PARD6A; involved in TGF-beta induced epithelial to mesenchymal transition. Interacts with SMAD7, NEDD4L, SMURF1 and SMURF2; SMAD7 recruits NEDD4L, SMURF1 and SMURF2 to the TGF-beta receptor. Interacts with USP15 and VPS39. Interacts with SDCBP (via C-terminus) (PubMed:25893292) Interacts with CAV1 and this interaction is impaired in the presence of SDCBP (PubMed:25893292). Interacts with APPL1; interaction is TGF beta dependent; mediates trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner (PubMed:26583432).TISSUE SPECIFICITY Found in all tissues examined, most abundant in placenta and least abundant in brain and heart. Expressed in a variety of cancer cell lines (PubMed:25893292).PTM Phosphorylated at basal levels in the absence of ligand. Activated upon phosphorylation by TGFBR2, mainly in the GS domain. Phosphorylation in the GS domain abrogates FKBP1A-binding.PTM N-Glycosylated.PTM Ubiquitinated; undergoes ubiquitination catalyzed by several E3 ubiquitin ligases including SMURF1, SMURF2 and NEDD4L2. Results in the proteasomal and/or lysosomal degradation of the receptor thereby negatively regulating its activity. Deubiquitinated by USP15, leading to stabilization of the protein and enhanced TGF-beta signal. Its ubiquitination and proteasome-mediated degradation is negatively regulated by SDCBP (PubMed:25893292).SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.CAUTION One report originally reported variant Ile-375 (PubMed:22113417). This variant has been subsequently corrected to Arg-375 by the same authors (Ref.49). UniProt P36897 O-phospho-L-serine at 165 165 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-threonine at 185 185 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-threonine at 186 186 EQUAL O-phospho-L-serine at 187 187 EQUAL O-phospho-L-serine at 189 189 EQUAL O-phospho-L-serine at 191 191 EQUAL 34 EQUAL 503 EQUAL Reactome Database ID Release 79 170863 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170863 Reactome R-HSA-170863 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170863.1 Reactome DB_ID: 170852 1 extracellular region GO 0005576 Dimeric TGFB1 [extracellular region] Dimeric TGFB1 Dimeric TGF-beta 1 Reactome DB_ID: 170838 2 UniProt:P01137 TGFB1 TGFB1 TGFB1 TGFB FUNCTION Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.SUBUNIT Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Interacts with the serine proteases, HTRA1 and HTRA3: the interaction with either inhibits TGFB1-mediated signaling and the HTRA protease activity is required for this inhibition (By similarity). May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling (By similarity). Interacts with CD109, DPT and ASPN (PubMed:9895299, PubMed:16754747, PubMed:17827158). Interacts with EFEMP2 (PubMed:27339457). Interacts with TSKU; the interaction contributes to regulation of the hair cycle (By similarity).TISSUE SPECIFICITY Highly expressed in bone (PubMed:11746498, PubMed:17827158). Abundantly expressed in articular cartilage and chondrocytes and is increased in osteoarthritis (OA) (PubMed:11746498, PubMed:17827158). Colocalizes with ASPN in chondrocytes within OA lesions of articular cartilage (PubMed:17827158).PTM Transforming growth factor beta-1 proprotein: The precursor proprotein is cleaved in the Golgi apparatus by FURIN to form Transforming growth factor beta-1 (TGF-beta-1) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-1 inactive.POLYMORPHISM In post-menopausal Japanese women, the frequency of Leu-10 is higher in subjects with osteoporosis than in controls.MISCELLANEOUS TGF-beta-1 is inactivated by fresolimumab (also named GC1008), a monoclonal-neutralizing antibody.SIMILARITY Belongs to the TGF-beta family. UniProt P01137 279 EQUAL 390 EQUAL Reactome Database ID Release 79 170852 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170852 Reactome R-HSA-170852 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170852.1 Reactome DB_ID: 170866 1 TGFBR2 homodimer [plasma membrane] TGFBR2 homodimer Type II receptor complex Reactome DB_ID: 170842 2 UniProt:P37173 TGFBR2 TGFBR2 TGFBR2 FUNCTION Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFRB1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways.SUBUNIT Homodimer. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGFRB1 and TGFRB2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Interacts with DAXX. Interacts with DYNLT4. Interacts with ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with and is activated by SCUBE3; this interaction does not affect TGFB1-binding to TGFBR2. Interacts with VPS39; this interaction is independent of the receptor kinase activity and of the presence of TGF-beta. Interacts with CLU (PubMed:8555189).PTM Phosphorylated on a Ser/Thr residue in the cytoplasmic domain.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily. UniProt P37173 23 EQUAL 567 EQUAL Reactome Database ID Release 79 170866 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170866 Reactome R-HSA-170866 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170866.1 Reactome Database ID Release 79 170841 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170841 Reactome R-HSA-170841 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170841.1 Reactome Database ID Release 79 173476 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=173476 Reactome R-HSA-173476 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-173476.2 Reactome DB_ID: 2162158 1 GADD34:PP1 [cytosol] GADD34:PP1 Converted from EntitySet in Reactome Reactome DB_ID: 163538 1 PP1 catalytic subunit [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PPP1CC [cytosol] PPP1CA [cytosol] PPP1CB [cytosol] UniProt P36873 UniProt P62136 UniProt P62140 Reactome DB_ID: 178231 1 UniProt:O75807 PPP1R15A PPP1R15A PPP1R15A GADD34 FUNCTION Recruits the serine/threonine-protein phosphatase PP1 to dephosphorylate the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress. Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1. May promote apoptosis by inducing TP53 phosphorylation on 'Ser-15'.SUBUNIT Interacts with PCNA (By similarity). Interacts with LYN and KMT2A/MLL1. Interacts with PP1, PPP1R1A and SMARCB1. Interacts with SMAD7. Interacts with BAG1.INDUCTION Specifically produced in response to stress: in absence of stress, some upstream open reading frame (uORF) of this transcript is translated, thereby preventing its translation (PubMed:19131336). By methyl methanesulfonate and ionizing irradiation (PubMed:9153226). By IL24/interleukin-24 in melanoma cells; which induces apoptosis (PubMed:10490642, PubMed:12114539).PTM Phosphorylated at multiple Ser/Thr residues. Phosphorylated on tyrosine by LYN; which impairs its antiproliferative activity. Phosphorylation at Tyr-262 enhances proteasomal degradation, this position is dephosphorylated by PTPN2.PTM Polyubiquitinated. Exhibits a rapid proteasomal degradation with a half-life under 1 hour, ubiquitination depends on endoplasmic reticulum association.MISCELLANEOUS The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.SIMILARITY Belongs to the PPP1R15 family. UniProt O75807 1 EQUAL 674 EQUAL Reactome Database ID Release 79 2162158 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162158 Reactome R-HSA-2162158 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2162158.1 Reactome DB_ID: 206180 1 UniProt:O95405-1 ZFYVE9 ZFYVE9 ZFYVE9 MADHIP SMADIP SARA FUNCTION Early endosomal protein that functions to recruit SMAD2/SMAD3 to intracellular membranes and to the TGF-beta receptor. Plays a significant role in TGF-mediated signaling by regulating the subcellular location of SMAD2 and SMAD3 and modulating the transcriptional activity of the SMAD3/SMAD4 complex. Possibly associated with TGF-beta receptor internalization.SUBUNIT Interacts (via the SBD region) with SMAD2; the interaction recruits SMAD2 to the TGF-beta receptor and is disrupted by phosphorylation of SMAD2 upon TGF-beta receptor activation. Interacts with SMAD3. Interacts with TGFBR1 and TGFBR2; the interaction recruits SMAD2 to the TGF-beta receptor. Interacts with PML.TISSUE SPECIFICITY Ubiquitous. In the brain found primarily in the cerebrovascular smooth muscle cells and reactive astrocytes.DOMAIN The SMAD binding domain (SBD) interacts with the MH2 domains of SMAD2 or SMAD3.DOMAIN The FYVE-type zinc finger is necessary and sufficient for its localization into early endosomes and mediates the association with PI3P. UniProt O95405-1 1 EQUAL 1425 EQUAL Reactome Database ID Release 79 2167884 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2167884 Reactome R-HSA-2167884 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2167884.1 Reactome DB_ID: 29356 6 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 29372 6 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 Reactome DB_ID: 173478 1 1 EQUAL 426 EQUAL Reactome DB_ID: 206180 1 1 EQUAL 1425 EQUAL Reactome DB_ID: 2162158 1 Reactome DB_ID: 2167873 1 TGFB1:TGFBR2:TGFBR1 [early endosome membrane] TGFB1:TGFBR2:TGFBR1 TGF-beta 1:type II receptor:type I receptor complex Reactome DB_ID: 170852 1 Reactome DB_ID: 170866 1 Reactome DB_ID: 170864 1 TGFBR1 homodimer [plasma membrane] TGFBR1 homodimer Type I receptor dimer Reactome DB_ID: 170839 2 34 EQUAL 503 EQUAL Reactome Database ID Release 79 170864 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170864 Reactome R-HSA-170864 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170864.1 Reactome Database ID Release 79 2167873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2167873 Reactome R-HSA-2167873 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2167873.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2167884 GO 0004721 GO molecular function Reactome Database ID Release 79 178169 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=178169 Reactome Database ID Release 79 178178 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=178178 Reactome R-HSA-178178 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-178178.2 14718519 Pubmed 2004 GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor Shi, W Sun, C He, B Xiong, W Shi, X Yao, D Cao, X J Cell Biol 164:291-300