BioPAX pathway converted from "Smad7 recruits GADD34:PP1CC to phosphorylated TGF-beta receptor complex" in the Reactome database. Smad7 recruits GADD34:PP1CC to phosphorylated TGF-beta receptor complex Smad7 recruits GADD34:PP1CC to phosphorylated TGF-beta receptor complex Full length mouse Smad7 was used to screen a human chondrocyte cDNA library in a yeast two-hybrid system and PPP1R15A (GADD34) was identified as a binding partner of Smad7. The interaction was confirmed by cotransfection of mouse Smad7 and human PPP1R15A (GADD34) into COS1 cells. The association was positively affected by TGF-beta treatment. Exogenously expressed human TGFB1 receptors and catalytic subunit of PP1, PP1CC, could also be identified in the complex of Smad7 and GADD34. Formation of a complex of TGF-beta receptors, Smad7 and PP1 was dependent on the function of SARA, as shown by expression of dominant negative SARA mutants in COS1 cells. SARA interacts with the catalytic subunit of PP1, likely serving as a membrane anchor for PP1CC (Shi et al. 2004). 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: 206180 1 early endosome membrane GO 0031901 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. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt O95405-1 Chain Coordinates 1 EQUAL 1425 EQUAL Reactome DB_ID: 2162160 1 cytosol GO 0005829 GADD34:PP1CC [cytosol] GADD34:PP1CC Reactome DB_ID: 163443 1 UniProt:P36873 PPP1CC PPP1CC PPP1CC FUNCTION Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Dephosphorylates RPS6KB1. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208).ACTIVITY REGULATION Inactivated by binding to URI1. The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.SUBUNIT PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, which is folded into its native form by inhibitor 2 and glycogen synthetase kinase 3, and then complexed to one or several targeting or regulatory subunits. PPP1R12A, PPP1R12B and PPP1R12C mediate binding to myosin. PPP1R3A (in skeletal muscle), PPP1R3B (in liver), PPP1R3C, PPP1R3D and PPP1R3F (in brain) mediate binding to glycogen. Interacts with cyanobacterial toxin microcystin; disulfide-linked. Interacts with PPP1R3B and PPP1R7. Isoform 2 interacts with SPZ1 (By similarity). Interacts with CDCA2. PPP1R15A and PPP1R15B mediate binding to EIF2S1. Part of a complex containing PPP1R15B, PP1 and NCK1/2. Interacts with IKFZ1; the interaction targets PPP1CC to pericentromeric heterochromatin, dephosphorylates IKAROS, stabilizes it and prevents it from degradation. Interacts with PPP1R42; the interaction is direct (By similarity). Interacts with NOM1 and PPP1R8. Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R8. Interacts with isoform 1 and isoform 4 NEK2. Interacts with URI1; the interaction is phosphorylation-dependent and occurs in a growth factor-dependent manner. Interacts with FOXP3. Interacts with TMEM225 (via RVxF motif) (By similarity). Interacts with MKI67 (PubMed:24867636). Interacts with RRP1B; this targets PPP1CC to the nucleolus (PubMed:20926688). Interacts with PPP1R2B (PubMed:23506001). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (PubMed:23846654). Interacts with DYNLT4 (PubMed:23789093).INDUCTION Up-regulated in synovial fluid mononuclear cells and peripheral blood mononuclear cells from patients with rheumatoid arthritis.PTM Phosphorylated by NEK2.MISCELLANEOUS Microcystin toxin is bound to Cys-273 through a thioether bond.SIMILARITY Belongs to the PPP phosphatase family. PP-1 subfamily.CAUTION Was originally thought to be part of the MLL5-L complex, at least composed of KMT2E, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and OGT (PubMed:19377461). However, the corresponding article has been retracted (PubMed:24336203). UniProt P36873 2 EQUAL 323 EQUAL 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 2162160 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=2162160 Reactome R-HSA-2162160 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-2162160.1 Reactome DB_ID: 2167878 1 plasma membrane GO 0005886 TGFB1:p-TGFBR:Smad7 [plasma membrane] TGFB1:p-TGFBR:Smad7 TGFB1:TGFBR2:p-TGFBR1:Smad7 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 DB_ID: 2161209 1 UniProt:O35253 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 COPS5. Interacts with STAMBP. Interacts with PPP1R15A (By similarity). Interacts with NEDD4L. Interacts with RNF111, AXIN1 and AXIN2. Interacts with ACVR1B, SMURF1, SMURF2 and TGFBR1; SMAD7 recruits SMURF1 and SMURF2 to the TGF-beta receptor and regulates its degradation (By similarity). Interacts with WWP1. Interacts with PDPK1 (via PH domain) (By similarity). Ubiquitinated by WWP1.TISSUE SPECIFICITY Ubiquitous in various organs, with higher levels in brain and kidney.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 (PubMed:11278814). Phosphorylated by PDPK1 (By similarity).PTM Ubiquitinated by WWP1 (PubMed:15221015). Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation (PubMed:14657019). In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation (By similarity). Ubiquitinated by RNF165, promoting proteasomal degradation, leading to enhance the BMP-Smad signaling (PubMed:23610558).PTM Acetylation prevents ubiquitination and degradation mediated by SMURF1.SIMILARITY Belongs to the dwarfin/SMAD family. Mus musculus NCBI Taxonomy 10090 UniProt O35253 1 EQUAL 426 EQUAL Reactome Database ID Release 79 2167878 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=2167878 Reactome R-NUL-2167878 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-NUL-2167878.1 Reactome DB_ID: 2167871 1 TGFB1:p-TGFBR:Smad7:GADD34:PP1CC:SARA [early endosome membrane] TGFB1:p-TGFBR:Smad7:GADD34:PP1CC:SARA Reactome DB_ID: 206180 1 1 EQUAL 1425 EQUAL Reactome DB_ID: 2162160 1 Reactome DB_ID: 2167878 1 Reactome Database ID Release 79 2167871 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=2167871 Reactome R-NUL-2167871 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-NUL-2167871.1 Reactome Database ID Release 79 2167890 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=2167890 Reactome R-NUL-2167890 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-NUL-2167890.1 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