BioPAX pathway converted from "An anchoring protein, Endofin, recruits R-Smad1/5/8" in the Reactome database.LEFT-TO-RIGHTAn anchoring protein, Endofin, recruits R-Smad1/5/8Endofin is a FYVE domain-containing protein that strongly resembles SARA, the Smad anchor for receptor activation that facilitates TGF-beta signalling. Endofin acts in a similar manner as SARA, it binds to BMP-specific R-Smads, it localizes in early endosomes and it facilitates their phosphorylation, thus promoting signal transduction by the BMP receptors. However, it should be noted that endofin has also been reported to bind to the Co-Smad, Smad4, and to the TGF-beta type receptor, thus enhancing TGF-beta signalling. Since Smad4 is a common Smad that operates in the BMP-specific pathways, the latter observation might imply that endofin could regulate both TGF-beta and BMP signalling, a hypothesis still open for investigation.Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00Reviewed: Heldin, CH, 2007-11-12Edited: Jassal, B, 2007-09-03 13:27:21BMP:BMPRII:P-BMPRIBMP:BMPRII:p-4S-BMPRIDimeric BMP2:BMP type II receptor:Phospho-BMP type I receptor complexReactome DB_ID: 201426plasma membraneGENE ONTOLOGYGO:0005886p-4S-BMPRI dimerPhospho-BMP type I receptor dimerReactome DB_ID: 201447Converted from EntitySet in Reactomep-4S-BMPRIPhospho-Type I receptorReactome DB_ID: 201826BMPR1Ap-4S-BMPR1Ap-S215,S216,S218,S220-BMPR1APhospho-Bone morphogenetic protein receptor type IABMRA_HUMANReactome DB_ID: 201448UniProt:P36894 BMPR1ABMPR1AACVRLK3ALK3FUNCTION On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP2, BMP4, GDF5 and GDF6. Positively regulates chondrocyte differentiation through GDF5 interaction. Mediates induction of adipogenesis by GDF6.SUBUNIT Interacts with BMP2 (PubMed:10881198, PubMed:18937504). Interacts with low affinity with GDF5; positively regulates chondrocyte differentiation (PubMed:24098149).TISSUE SPECIFICITY Highly expressed in skeletal muscle.PTM Glycosylated.DISEASE A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.Homo sapiensNCBI Taxonomy9606UniProtP36894215EQUALO-phospho-L-serineMODMOD:00046216EQUAL218EQUAL220EQUAL24EQUAL532EQUALReactome Database ID Release 76201448Database 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=201448ReactomeR-HSA-2014481Reactome 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-201448.1Reactomehttp://www.reactome.orgBMPR1Bp-4S-BMPR1BPhospho-Bone morphogenetic protein receptor type IBBMRB_HUMANReactome DB_ID: 201814UniProt:O00238 BMPR1BBMPR1BFUNCTION On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP7/OP-1 and GDF5. Positively regulates chondrocyte differentiation through GDF5 interaction.SUBUNIT Interacts with high affinity with GDF5; positively regulates chondrocyte differentiation.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.UniProtO0023814EQUAL502EQUALReactome Database ID Release 76201814Database 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=201814ReactomeR-HSA-2018141Reactome 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-201814.1Reactome Database ID Release 76201826Database 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=201826ReactomeR-HSA-2018261Reactome 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-201826.12Reactome Database ID Release 76201447Database 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=201447ReactomeR-HSA-2014471Reactome 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-201447.11BMP2 dimerReactome DB_ID: 201463extracellular regionGENE ONTOLOGYGO:0005576BMP2Bone morphogenetic protein 2BMP2_HUMANReactome DB_ID: 201456UniProt:P12643 BMP2BMP2BMP2AFUNCTION Induces cartilage and bone formation (PubMed:3201241). Stimulates the differentiation of myoblasts into osteoblasts via the EIF2AK3-EIF2A- ATF4 pathway. BMP2 activation of EIF2AK3 stimulates phosphorylation of EIF2A which leads to increased expression of ATF4 which plays a central role in osteoblast differentiation. In addition stimulates TMEM119, which upregulates the expression of ATF4 (PubMed:24362451).SUBUNIT Homodimer; disulfide-linked (PubMed:10074410). Interacts with SOSTDC1 (PubMed:15020244). Interacts with GREM2, RGMA, RGMB and RGMC. Interacts with ASPN (By similarity). Interacts with MAFP5 (By similarity). Interacts with FBN1 (via N-terminal domain) and FBN2 (PubMed:18339631).TISSUE SPECIFICITY Particularly abundant in lung, spleen and colon and in low but significant levels in heart, brain, placenta, liver, skeletal muscle, kidney, pancreas, prostate, ovary and small intestine.PHARMACEUTICAL Available under the name Infuse (Medtronic Sofamor Danek). Used for treating open tibial shaft fractures.SIMILARITY Belongs to the TGF-beta family.UniProtP12643283EQUAL396EQUALReactome Database ID Release 76201456Database 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=201456ReactomeR-HSA-2014561Reactome 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-201456.12Reactome Database ID Release 76201463Database 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=201463ReactomeR-HSA-2014632Reactome 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-201463.21BMPRII dimerBMP type II receptor dimerReactome DB_ID: 201465Converted from EntitySet in ReactomeType II receptorReactome DB_ID: 201804ACVR2ACVR2AActivin receptor type IIAVR2_HUMANReactome DB_ID: 201659UniProt:P27037 ACVR2AACVR2AACVR2FUNCTION On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin A, activin B and inhibin A. Mediates induction of adipogenesis by GDF6 (By similarity).SUBUNIT Interacts with AIP1. Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3 (By similarity).SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.UniProtP2703720EQUAL513EQUALReactome Database ID Release 76201659Database 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=201659ReactomeR-HSA-2016591Reactome 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-201659.1ACVR2BActivin receptor type IIBAVRB_HUMANReactome DB_ID: 201656UniProt:Q13705 ACVR2BACVR2BFUNCTION Transmembrane serine/threonine kinase activin type-2 receptor forming an activin receptor complex with activin type-1 serine/threonine kinase receptors (ACVR1, ACVR1B or ACVR1c). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, the type-2 receptors act as a primary activin receptors (binds activin-A/INHBA, activin-B/INHBB as well as inhibin-A/INHA-INHBA). The type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine-threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C-terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor.SUBUNIT Forms an activin receptor complex with activin type II receptors such as ACVR1B. Interacts with VPS39. Interacts with DYNLT1.PTM Phosphorylated. Constitutive phosphorylation is in part catalyzed by its own kinase activity.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.UniProtQ1370519EQUAL512EQUALReactome Database ID Release 76201656Database 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=201656ReactomeR-HSA-2016561Reactome 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-201656.1BMPR2Bone morphogenetic protein receptor type IIBMR2_HUMANReactome DB_ID: 201442UniProt:Q13873 BMPR2BMPR2PPH1FUNCTION On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Binds to BMP7, BMP2 and, less efficiently, BMP4. Binding is weak but enhanced by the presence of type I receptors for BMPs. Mediates induction of adipogenesis by GDF6.SUBUNIT Interacts with GDF5.TISSUE SPECIFICITY Highly expressed in heart and liver.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.UniProtQ1387327EQUAL1038EQUALReactome Database ID Release 76201442Database 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=201442ReactomeR-HSA-2014421Reactome 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-201442.1Reactome Database ID Release 76201804Database 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=201804ReactomeR-HSA-2018041Reactome 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-201804.12Reactome Database ID Release 76201465Database 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=201465ReactomeR-HSA-2014651Reactome 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-201465.11Reactome Database ID Release 76201426Database 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=201426ReactomeR-HSA-2014261Reactome 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-201426.1Converted from EntitySet in ReactomeSMAD1/5/8R-Smad1/5/8Reactome DB_ID: 201424SMAD1R-Smad1Mothers against decapentaplegic homolog 1SMA1_HUMANReactome DB_ID: 201468cytosolGENE ONTOLOGYGO:0005829UniProt: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.UniProtQ157971EQUAL465EQUALReactome Database ID Release 76201468Database 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=201468ReactomeR-HSA-2014681Reactome 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-201468.1SMAD5R-Smad5Mothers against decapentaplegic homolog 5SMA5_HUMANReactome DB_ID: 201431UniProt: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.UniProtQ997172EQUAL465EQUALReactome Database ID Release 76201431Database 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=201431ReactomeR-HSA-2014311Reactome 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-201431.1SMAD9r-SMAD8R-SMAD9Mothers against decapentaplegic homolog 9SMA9_HUMANReactome DB_ID: 201478UniProt: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.UniProtO151981EQUAL467EQUALReactome Database ID Release 76201478Database 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=201478ReactomeR-HSA-2014781Reactome 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-201478.1Reactome Database ID Release 76201424Database 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=201424ReactomeR-HSA-2014241Reactome 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-201424.1ZFYVE16EndofinZinc finger FYVE domain-containing protein 16ZY16_HUMANReactome DB_ID: 201645early endosome membraneGENE ONTOLOGYGO:0031901UniProt:Q7Z3T8 ZFYVE16ZFYVE16KIAA0305FUNCTION May be involved in regulating membrane trafficking in the endosomal pathway. Overexpression induces endosome aggregation. Required to target TOM1 to endosomes.SUBUNIT Interacts with the C-terminus of TOM1. Does not interact with TOM1L1 or TOM1L2.TISSUE SPECIFICITY Widely expressed. Highly expressed in kidney, placenta and lung. Expressed at intermediate level in heart, brain, skeletal muscle, spleen and liver. Weakly expressed in colon, thymus and peripheral blood lymphocytes.DOMAIN The FYVE-type zinc finger is necessary and sufficient for its localization into early endosomes and mediates the association with PI3P.UniProtQ7Z3T81EQUAL1539EQUALReactome Database ID Release 76201645Database 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=201645ReactomeR-HSA-2016451Reactome 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-201645.1BMP:p-BMPR:Endofin:SMAD1/5/8BMP2:BMP type II receptor:Phospho-BMP type I receptor:Endofin:R-SMAD1/5/8Reactome DB_ID: 201477111Reactome Database ID Release 76201477Database 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=201477ReactomeR-HSA-2014772Reactome 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-201477.2Reactome Database ID Release 76201648Database 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=201648ReactomeR-HSA-2016482Reactome 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-201648.217356069Pubmed2007Endofin acts as a Smad anchor for receptor activation in BMP signalingShi, WChang, CNie, SXie, SWan, MCao, XJ Cell Sci 120:1216-24