BioPAX pathway converted from "SKI complexes with the Smad complex, suppressing BMP2 signalling" in the Reactome database.LEFT-TO-RIGHTSKI complexes with the Smad complex, suppressing BMP2 signallingSKI and SKIL (SNO) are able to recruit NCOR and possibly other transcriptional repressors to SMAD2/3:SMAD4 complex, inhibiting SMAD2/3:SMAD4-mediated transcription (Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999). Experimental findings suggest that SMAD2 and SMAD3 may target SKI and SKIL for degradation (Strochein et al. 1999, Sun et al. 1999 PNAS, Bonni et al. 2001), and that the ratio of SMAD2/3 and SKI/SKIL determines the outcome (inhibition of SMAD2/3:SMAD4-mediated transcription or degradation of SKI/SKIL). SKI and SKIL are overexpressed in various cancer types and their oncogenic effect is connected with their ability to inhibit signaling by TGF-beta receptor complex. Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00Reviewed: Heldin, CH, 2007-11-12p-2S-SMAD1/5/8:SMAD4Phospho-r-SMAD1/5/8:Co-SMAD complexReactome DB_ID: 201450nucleoplasmGENE ONTOLOGYGO:0005654SMAD4Co-SMADMothers against decapentaplegic homolog 4Reactome DB_ID: 177103UniProt:Q13485 SMAD4SMAD4DPC4MADH4FUNCTION In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Monomer; in the absence of TGF-beta activation (PubMed:9670020). Heterotrimer; on TGF-beta activation (PubMed:15799969). Heterotrimer composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex (PubMed:15799969, PubMed:15350224). Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Found in a complex with SMAD1 and YY1 (By similarity). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Interacts with CITED1 and CITED2. Interacts with PDPK1 (via PH domain) (By similarity). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains) (PubMed:24324267). Interacts with ZC3H3 (By similarity). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725). Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix (PubMed:25310401). Interacts with DLX1 (PubMed:14671321). Interacts with ZBTB7A; the interaction is direct and stimulated by TGFB1 (PubMed:25514493). Interacts with CREBBP; the recruitment of this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with EP300; the interaction with this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with HDAC1 (PubMed:25514493). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850).DOMAIN The MH1 domain is required for DNA binding.DOMAIN The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.PTM Phosphorylated by PDPK1.PTM Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling.DISEASE SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.SIMILARITY Belongs to the dwarfin/SMAD family.Homo sapiensNCBI Taxonomy9606UniProtQ134851EQUAL552EQUALReactome Database ID Release 76177103Database 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=177103ReactomeR-HSA-1771031Reactome 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-177103.1Reactomehttp://www.reactome.org1Converted from EntitySet in ReactomePhospho-R-SMAD1/5/9Reactome DB_ID: 201444SMA1_HUMANp-S463,S465-SMAD1Phospho-R-SMAD1Mothers against decapentaplegic homolog 1Reactome DB_ID: 201483UniProt:Q15797 SMAD1SMAD1BSP1MADH1MADR1FUNCTION Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD1 is a receptor-regulated SMAD (R-SMAD). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1. May act synergistically with SMAD4 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression.SUBUNIT Found in a complex with SMAD4 and YY1. Interacts with HGS, NANOG and ZCCHC12 (By similarity). Upon C-terminus phosphorylation: forms trimers with another SMAD1 and the co-SMAD SMAD4. Interacts with PEBP2-alpha subunit, CREB-binding protein (CBP), p300, SMURF1, SMURF2, USP15 and HOXC8. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with SKOR1. Interacts (via MH2 domain) with LEMD3. Binding to LEMD3 results in at least a partial reduction of receptor-mediated phosphorylation. Forms a ternary complex with PSMB4 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Found in a macromolecular complex with FAM83G. Interacts (via MH2 domain) with FAM83G (via MH2 domain); in a SMAD4-independent manner. Interacts with ZC3H3 (By similarity). Interacts with TMEM119 (By similarity). Interacts (via MH1 and MH2 domains) with ZNF8 (By similarity). Interacts with RANBP3L; the interaction increases when SMAD1 is not phosphorylated and mediates SMAD1 nuclear export (PubMed:25755279).TISSUE SPECIFICITY Ubiquitous. Highest expression seen in the heart and skeletal muscle.DOMAIN The MH2 domain mediates phosphorylation-dependent trimerization through L3 loop binding of phosphoserines in the adjacent subunit.PTM Phosphorylation of the C-terminal SVS motif by BMP type 1 receptor kinase activates SMAD1 by promoting dissociation from the receptor and trimerization with SMAD4.PTM Ubiquitinated by SMAD-specific E3 ubiquitin ligase SMURF1, leading to its degradation. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes. Dephosphorylation, probably by PPM1A, induces its export from the nucleus to the cytoplasm (By similarity).DISEASE SMAD1 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.SIMILARITY Belongs to the dwarfin/SMAD family.UniProtQ15797463EQUALO-phospho-L-serineMODMOD:00046465EQUAL1EQUAL465EQUALReactome Database ID Release 76201483Database 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=201483ReactomeR-HSA-2014831Reactome 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-201483.1SMA5_HUMANp-S463,S465-SMAD5Phospho-R-SMAD5Mothers against decapentaplegic homolog 5Reactome DB_ID: 201432UniProt:Q99717 SMAD5SMAD5MADH5FUNCTION Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD5 is a receptor-regulated SMAD (R-SMAD).SUBUNIT May form trimers with the co-SMAD SMAD4. Interacts with PEBP2-alpha subunit and SMURF1. Interacts with SUV39H1 and SUV39H2. Interacts (via MH2 domain) with LEMD3. Interacts with WWP1. Interacts with TMEM119 (By similarity). Interacts with ZNF8 (PubMed:12370310). Interacts with RANBP3L (PubMed:25755279).TISSUE SPECIFICITY Ubiquitous.PTM Phosphorylated on serine by BMP (bone morphogenetic proteins) type 1 receptor kinase.PTM Ubiquitin-mediated proteolysis by SMAD-specific E3 ubiquitin ligase SMURF1.SIMILARITY Belongs to the dwarfin/SMAD family.UniProtQ99717463EQUAL465EQUAL2EQUAL465EQUALReactome Database ID Release 76201432Database 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=201432ReactomeR-HSA-2014321Reactome 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-201432.1SMA9_HUMANp-S465,S467-SMAD9Phospho-R-SMAD9Mothers against decapentaplegic homolog 9Reactome DB_ID: 201474UniProt:O15198 SMAD9SMAD9MADH6MADH9SMAD8FUNCTION Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD9 is a receptor-regulated SMAD (R-SMAD).SUBUNIT Interaction with the co-SMAD SMAD4. Interacts with PEBP2-alpha subunit. Interacts with RANBP3L (PubMed:25755279).TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, skeletal muscle, prostate, testis, ovary and small intestine. Also expressed in fetal brain, lung and kidney.PTM Phosphorylated on serine by BMP (bone morphogenetic proteins) type 1 receptor kinase.SIMILARITY Belongs to the dwarfin/SMAD family.UniProtO15198465EQUAL467EQUAL1EQUAL467EQUALReactome Database ID Release 76201474Database 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=201474ReactomeR-HSA-2014741Reactome 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-201474.1Reactome Database ID Release 76201444Database 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=201444ReactomeR-HSA-2014441Reactome 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-201444.12Reactome Database ID Release 76201450Database 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=201450ReactomeR-HSA-2014502Reactome 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-201450.2SKISki oncogeneReactome DB_ID: 173473UniProt:P12755 SKISKIFUNCTION May play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage. Functions as a repressor of TGF-beta signaling.SUBUNIT Interacts with SMAD2, SMAD3 and SMAD4. Interacts with HIPK2. Part of a complex with HIPK2 and SMAD1/2/3. Interacts with PRDM16 and SMAD3; the interaction with PRDM16 promotes the recruitment SMAD3-HDAC1 complex on the promoter of TGF-beta target genes.PTM Ubiquitinated by RNF165, promoting proteasomal degradation, leading to enhance the BMP-Smad signaling.SIMILARITY Belongs to the SKI family.UniProtP127551EQUAL728EQUALReactome Database ID Release 76173473Database 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=173473ReactomeR-HSA-1734731Reactome 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-173473.1p-2S-SMAD1/5/8:SMAD4:SKIPhospho-r-SMAD1/5/8:Co-SMAD:SKIReactome DB_ID: 20142711Reactome Database ID Release 76201427Database 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=201427ReactomeR-HSA-2014272Reactome 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-201427.2Reactome Database ID Release 76201423Database 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=201423ReactomeR-HSA-2014233Reactome 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-201423.310485843Pubmed1999The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signalingLuo, KStroschein, SLWang, WeiChen, DanMartens, EZhou, SZhou, QGenes Dev 13:2196-20611121043Pubmed2000Ski represses bone morphogenic protein signaling in Xenopus and mammalian cellsWang, WMariani, FVHarland, RMLuo, KProc Natl Acad Sci U S A 97:14394-911389444Pubmed2001TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradationBonni, SWang, HRCausing, CGKavsak, PStroschein, SLLuo, KWrana, JLNat Cell Biol 3:587-9510549282Pubmed1999Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signalingSun, YLiu, XEaton, ENLane, WSLodish, HFWeinberg, RAMol Cell 4:499-50910531062Pubmed1999Negative feedback regulation of TGF-beta signaling by the SnoN oncoproteinStroschein, SLWang, WeiZhou, SZhou, QLuo, KScience 286:771-410535941Pubmed1999SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signalingSun, YLiu, XNg-Eaton, ELodish, HFWeinberg, RAProc Natl Acad Sci U S A 96:12442-7GENE ONTOLOGYGO:0030514gene ontology term for cellular processMIMI:0359