Signaling by BMP (Homo sapiens)

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7, 8261, 2110, 193, 16185, 17, 3091420, 229, 15276, 25, 314, 13, 2912, 2916, 19, 26112, 23, 28nucleoplasmearly endosomecytosolGene expression regulationBMP:p-BMPR:Endofin:p-2S-SMAD1/5/8BMP2 ACVR2A AMHR2 dimerUBE2D1 Ligand Trap:BMP2p-S465,S467-SMAD9 p-4S-BMPR1A SMURF2 BMPR2 SMURF1 SMAD7 SMURF1 SMURF2 ACVR2B p-S463,S465-SMAD5 p-4S-BMPR1B ACVR2A p-S463,S465-SMAD5 p-S463,S465-SMAD1 p-4S-BMPR1B p-4S-BMPR1B BMP2 BMPR1A p-S463,S465-SMAD1 p-2S-SMAD1/5/8:SMAD4:SKIGDF2 SMAD6 SMAD4SMAD4 BMPR2 BMP2 BMP2 dimerACVR2A I-SMAD:SMURFBMPR2 ACVR2B BMP2 SMAD6 p-S463,S465-SMAD5 BMP:p-BMPR:Endofin:SMAD1/5/8ACVR2A SMAD5 SMAD4 BMP2 SKIp-2S-SMAD1/5/8:SMAD4p-S463,S465-SMAD1 p-S463,S465-SMAD1 CHRDL1 GDF2 I-SMADSMAD7 p-4S-BMPR1A FSTL1 BMP2 p-S465,S467-SMAD9 SMURF2 ATPBMP2 BMP2:BMPtypeIIreceptor:Phospho-BMP type I receptor:I-SMADp-2S-SMAD1/5/8SMAD9 p-S465,S467-SMAD9 p-S463,S465-SMAD1 ACVRL1BMPR1B ACVR2A BMPR1B SKI p-4S-BMPR1B NOG GREM2 GREM2 BMP10 BMPRII:BMPRIFSTL1 CER1 BMP:p-BMPR:I-SMAD:SMURFACVR2B Nuclear ubiquitinligaseAMH BMPRI dimerp-4S-BMPR1A SMAD1 p-2S-SMAD1/5/8:SMAD4NOG BMP:BMPRII:p-4S-BMPRIACVR2A SMAD6 SMAD6 p-S463,S465-SMAD5 p-4S-BMPR1A SMAD5 p-S465,S467-SMAD9 p-S463,S465-SMAD5 SMAD7 SMAD1 p-4S-BMPR1A BMPR2 BMPR2 ACVR2B SMAD7 AMHR2 p-4S-BMPR1B BMP2 AMH dimerBMP10 AMHR2 BMPR2 ACVR2B BMPRII dimerBMPR2 AMH dimer:AMHR2dimerp-4S-BMPR1A SMAD6 I-SMAD:p-2S-SMAD1/5/8p-4S-BMPR1B ZFYVE16 BMPR1A ZFYVE16 SMURF1 BMPR2 ZFYVE16ADPATPACVR2A SMURFBMP2 ACVR2B p-S463,S465-SMAD1 BMP:p-BMPR:EndofinACVR2B CHRDL1 ACVRL1 SMAD9 SMAD4 GDF2 dimer, BMP10dimerACVR2A SMAD7 ACVR2A SMAD1/5/8CER1 ACVR2B ACVRL1:GDF2 dimer,BMP10 dimerACVR2B p-S463,S465-SMAD5 ADPp-S465,S467-SMAD9 Ligand Trapp-S465,S467-SMAD9 AMH BMPR1A BMPR2 BMPR1B UBE2D3 ZFYVE16 BMP:BMPRII:BMPRI24


Bone morphogenetic proteins (BMPs) have many biological activities in various tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. They are members of the Transforming growth factor-Beta (TGFB) family. They bind to type II and type I serine-threonine kinase receptors, which transduce signals through SMAD and non-SMAD signalling pathways. BMP signalling is linked to a wide variety of clinical disorders, including vascular diseases, skeletal diseases and cancer. BMPs typically activate BMP type I receptors and signal via SMAD1, 5 and 8. They can be classified into several subgroups, including the BMP2/4 group, the BMP5-8 osteogenic protein-1 (OP1) group, the growth and differentiation factor (GDF) 5-7 group and the BMP9/10 group. Most of the proteins of the BMP2/4, OP1 and BMP9/10 groups induce formation of bone and cartilage tissues in vivo, while the GDF5-7 group induce cartilage and tendon-like, but not bone-like, tissues (Miyazono et al. 2010). Members of the TGFB family bind to two types of serine-threonine kinase receptors, type I and type II (Massagué 2012). BMPs can bind type I receptors in the absence of type II receptors, but both types are required for signal transduction. The presence of both types dramatically increases binding affinity (Rozenweig et al. 1995). The type II receptor kinase transphosphorylates the type I receptor, which transmits specific intracellular signals. Type I and type II receptors share similar structural properties, comprised of a relatively short extracellular domain, a single membrane-spanning domain and an intracellular domain containing a serine-threonine kinase domain. Seven receptors, collectively referred to as the Activin receptor-like kinases (ALK), have been identified as type I receptors for the TGFB family in mammals. ALKs are classified into three groups based on their structure and function, the BMPRI group (Bone morphogenetic protein receptor type-1A, ALK3, BMPR1A and Bone morphogenetic protein receptor type-1B, ALK6, BMPR1B), the ALK1 group (Serine/threonine-protein kinase receptor R3, ALK1, ACVRL1 and Activin receptor type-1, ALK2, ACVR1) and the TBetaR1 group (Activin receptor type-1B, ALK4, ACVR1B and TGF-beta receptor type-1, ALK5, TGFBR1 and Activin receptor type-1C, ALK7, ACVR1C) (Kawabata et al. 1998). ALK1 group and BMPRI group activate SMAD1/5/8 and transduce similar intracellular signals. The TBetaR1 group activate SMAD2/3. BMPR1A and ACVR1 are widely expressed. BMPR1B shows a more restricted expression profile. ACVRL1 is limited to endothelial cells and a few other cell types. The binding specificities of BMPs to type I receptors is affected by the type II receptors that are present (Yu et al. 2005). Typically, BMP2 and BMP4 bind to BMPR1A and BMPR1B (ten Dijke et al. 1994). BMP6 and BMP7 bind strongly to ACVR1 and weakly to BMPR1B. Growth/differentiation factor 5 (BMP14, GDF5) preferentially binds to BMPR1B, but not to other type I receptors (Nishitoh et al. 1995). BMP9 and BMP10 bind to ACVRL1 and ACVRL (Scharpfenecker et al. 2007). BMP type I receptors are shared by other members of the TGFB family. Three receptors, Bone morphogenetic protein receptor type-2 (BMPR2), Activin receptor type-2A (ACVR2A) and Activin receptor type-2B (ACVR2B) are the type II receptors for mammalian BMPs. They are widely expressed in various tissues. BMPR2 is specific for BMPs, whereas ACVR2A and ACVR2B are shared with activins and myostatin. BMP binding and signalling can be affected by coreceptors. Glycosylphosphatidylinositol (GPI)-anchored proteins of the repulsive guidance molecule (RGM) family, including RGMA, RGMB (DRAGON) and Hemojuvelin (HFE2, RGMC) are coreceptors for BMP2 and BMP4, enhancing signaling (Samad et al. 2005, Babitt et al. 2005, 2006). They interact with BMP type I and/or type II receptors and bind BMP2 and BMP4, but not BMP7 or TGFB1. BMP2/4 signalling normally involves BMPR2, not ACVR2A or ACVR2B. Cells transfected with RGMA use both BMPR2 and ACVR2A for BMP-2/4 signalling, suggesting that RGMA facilitates the use of ACVR2A by BMP2/4 (Xia et al. 2007). Endoglin (ENG) is a transmembrane protein expressed in proliferating endothelial cells. It binds various ligands including TGFB1/3, Activin-A and BMP2/7 (Barbara et al. 1999). It inhibits TGFB-induced responses and enhances BMP7-induced responses (Scherner et al. 2007). Mutations in ENG result in hereditary haemorrhagic telangiectasia (HHT1), also known as OslerWeberRendu disease, while mutations in ACVRL1 lead to HHT2, suggesting that they act in a common signalling pathway (McAllister et al. 1994, Johnson et al. 1996). BMP2 is a dimeric protein, having two receptor-binding motifs. One is a high-affinity binding site for BMPR1A, the other is a low-affinity binding site for BMPR2 (Kirsch et al. 2000). In the absence of ligand stimulation, small fractions of type II and type I receptors are present as preexisting homodimers and heterodimers on the cell surface. Ligand-binding increases oligomerization. The intracellular domains of type I receptors have a characteristic GS domain (glycine and serine-rich domain) located N-terminal to the serine-threonine kinase domains. Type II receptor kinases are constitutively active in the absence of ligand. Upon ligand binding, the type II receptor kinase phosphorylates the GS domain of the type I receptor, a critical event in signal transduction by the serine/threonine kinase receptors (Miyazono et al. 2010). Activation of the TGFBR1 receptor has been studied in detail. The inactive conformation is maintained by interaction between the GS domain, the N-terminal lobe and the activation loop of the kinase (Huse et al. 1999). When the GS domain is phosphorylated by the type II receptor kinase, the TGFBR1 kinase is converted to an active conformation. Mutations of Thr-204 in TGFBR1 and the corresponding Gln in BMP type I receptors lead to their constitutive activation. The L45 loop, in the kinase domain of type I receptors, specifically interacts with receptor-regulated Smads (R-Smads). Neurotrophic tyrosine kinase receptor type 3 (NT-3 growth factor receptor, TrkC, NTRK3) directly binds BMPR2, interfereing with its interaction with BMPR1A, which inhibits downstream signalling (Jin et al. 2007). Tyrosine-protein kinase transmembrane receptor ROR2 and BMPR1B form a heteromeric complex in a ligand independent fashion that modulatesGDF5-BMPR1B signalling by inhibition of Smad1/5 signalling (Sammar et al. 2004). Type I receptor kinases activated by the type II receptor kinases, phosphorylate R-Smads. R-Smads then form a complex with common-partner Smad (co-Smad) and translocate to the nucleus. The oligomeric Smad complexes regulate the transcription of target genes through interaction with various transcription factors and transcriptional coactivators or corepressors. Inhibitory Smads (I-Smads) negatively regulate the action of R-Smads and/or co-Smads. Eight different Smads have been identified in mammals. Smad1, Smad5 and Smad8 are R-Smads in BMP signalling pathways (BMP-specific R-Smads). Smad2 and Smad3 are R-Smads in TGFB/activin
signalling pathways. BMP receptors can phosphorylate Smad2 in certain types of cells (Murakami et al. 2009). Smad1, Smad5 and Smad8 are structurally highly similar to each other. The functional differences between them are largely unknown. Smad4 is the only co-Smad in mammals, shared by both BMP and TGFB/activin signalling pathways. Smad6 and Smad7 are I-Smads. View original pathway at Reactome.


Pathway is converted from Reactome ID: 201451
Reactome version: 75
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Reactome Author: Huminiecki, L, Moustakas, A

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  4. 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
  5. Lin X, Liang M, Feng XH.; ''Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling.''; PubMed Europe PMC Scholia
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  8. Miyazono K, Kamiya Y, Morikawa M.; ''Bone morphogenetic protein receptors and signal transduction.''; PubMed Europe PMC Scholia
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  14. Wang W, Mariani FV, Harland RM, Luo K.; ''Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells.''; PubMed Europe PMC Scholia
  15. Liu F, Ventura F, Doody J, Massagué J.; ''Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs.''; PubMed Europe PMC Scholia
  16. Kretzschmar M, Liu F, Hata A, Doody J, Massagué J.; ''The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase.''; PubMed Europe PMC Scholia
  17. 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
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  22. Heldin CH, ten Dijke P.; ''SMAD destruction turns off signalling.''; PubMed Europe PMC Scholia
  23. Xiao Z, Latek R, Lodish HF.; ''An extended bipartite nuclear localization signal in Smad4 is required for its nuclear import and transcriptional activity.''; PubMed Europe PMC Scholia
  24. Wang W, Yang L, Hu L, Li F, Ren L, Yu H, Liu Y, Xia L, Lei H, Liao Z, Zhou F, Xie C, Zhou Y.; ''Inhibition of UBE2D3 expression attenuates radiosensitivity of MCF-7 human breast cancer cells by increasing hTERT expression and activity.''; PubMed Europe PMC Scholia
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  27. Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A.; ''Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor.''; PubMed Europe PMC Scholia
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  30. Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH.; ''A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation.''; PubMed Europe PMC Scholia
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External references


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NameTypeDatabase referenceComment
ACVR2A ProteinP27037 (Uniprot-TrEMBL)
ACVR2B ProteinQ13705 (Uniprot-TrEMBL)
ACVRL1 ProteinP37023 (Uniprot-TrEMBL)
ACVRL1:GDF2 dimer, BMP10 dimerComplexR-HSA-8858621 (Reactome)
ACVRL1ProteinP37023 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
AMH ProteinP03971 (Uniprot-TrEMBL)
AMH dimer:AMHR2 dimerComplexR-HSA-8858303 (Reactome)
AMH dimerComplexR-HSA-8858326 (Reactome)
AMHR2 ProteinQ16671 (Uniprot-TrEMBL)
AMHR2 dimerComplexR-HSA-8858341 (Reactome)
ATPMetaboliteCHEBI:30616 (ChEBI)
BMP10 ProteinO95393 (Uniprot-TrEMBL)
BMP2 ProteinP12643 (Uniprot-TrEMBL)
BMP2 dimerComplexR-HSA-201463 (Reactome)

type II

receptor:Phospho-BMP type I receptor:I-SMAD
ComplexR-HSA-201446 (Reactome)
BMP:BMPRII:BMPRIComplexR-HSA-201459 (Reactome)
BMP:BMPRII:p-4S-BMPRIComplexR-HSA-201426 (Reactome)
BMP:p-BMPR:Endofin:SMAD1/5/8ComplexR-HSA-201477 (Reactome)
BMP:p-BMPR:Endofin:p-2S-SMAD1/5/8ComplexR-HSA-201467 (Reactome)
BMP:p-BMPR:EndofinComplexR-HSA-201647 (Reactome)
BMP:p-BMPR:I-SMAD:SMURFComplexR-HSA-201841 (Reactome)
BMPR1A ProteinP36894 (Uniprot-TrEMBL)
BMPR1B ProteinO00238 (Uniprot-TrEMBL)
BMPR2 ProteinQ13873 (Uniprot-TrEMBL)
BMPRI dimerComplexR-HSA-201428 (Reactome)
BMPRII dimerComplexR-HSA-201465 (Reactome)
BMPRII:BMPRIComplexR-HSA-202640 (Reactome)
CER1 ProteinO95813 (Uniprot-TrEMBL)
CHRDL1 ProteinQ9BU40 (Uniprot-TrEMBL)
FSTL1 ProteinQ12841 (Uniprot-TrEMBL)
GDF2 ProteinQ9UK05 (Uniprot-TrEMBL)
GDF2 dimer, BMP10 dimerComplexR-HSA-8858373 (Reactome)
GREM2 ProteinQ9H772 (Uniprot-TrEMBL)
I-SMAD:SMURFComplexR-HSA-178185 (Reactome)
I-SMAD:p-2S-SMAD1/5/8ComplexR-HSA-202644 (Reactome)
I-SMADComplexR-HSA-173495 (Reactome)
Ligand Trap:BMP2ComplexR-HSA-201806 (Reactome)
Ligand TrapComplexR-HSA-201828 (Reactome)
NOG ProteinQ13253 (Uniprot-TrEMBL)
Nuclear ubiquitin ligaseComplexR-HSA-173530 (Reactome)
SKI ProteinP12755 (Uniprot-TrEMBL)
SKIProteinP12755 (Uniprot-TrEMBL)
SMAD1 ProteinQ15797 (Uniprot-TrEMBL)
SMAD1/5/8ComplexR-HSA-201424 (Reactome)
SMAD4 ProteinQ13485 (Uniprot-TrEMBL)
SMAD4ProteinQ13485 (Uniprot-TrEMBL)
SMAD5 ProteinQ99717 (Uniprot-TrEMBL)
SMAD6 ProteinO43541 (Uniprot-TrEMBL)
SMAD7 ProteinO15105 (Uniprot-TrEMBL)
SMAD9 ProteinO15198 (Uniprot-TrEMBL)
SMURF1 ProteinQ9HCE7 (Uniprot-TrEMBL)
SMURF2 ProteinQ9HAU4 (Uniprot-TrEMBL)
SMURFComplexR-HSA-173533 (Reactome)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2D3 ProteinP61077 (Uniprot-TrEMBL)
ZFYVE16 ProteinQ7Z3T8 (Uniprot-TrEMBL)
ZFYVE16ProteinQ7Z3T8 (Uniprot-TrEMBL)
p-2S-SMAD1/5/8:SMAD4:SKIComplexR-HSA-201427 (Reactome)
p-2S-SMAD1/5/8:SMAD4ComplexR-HSA-201419 (Reactome)
p-2S-SMAD1/5/8:SMAD4ComplexR-HSA-201450 (Reactome)
p-2S-SMAD1/5/8ComplexR-HSA-201482 (Reactome)
p-4S-BMPR1A ProteinP36894 (Uniprot-TrEMBL)
p-4S-BMPR1B ProteinO00238 (Uniprot-TrEMBL)
p-S463,S465-SMAD1 ProteinQ15797 (Uniprot-TrEMBL)
p-S463,S465-SMAD5 ProteinQ99717 (Uniprot-TrEMBL)
p-S465,S467-SMAD9 ProteinO15198 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ACVRL1:GDF2 dimer, BMP10 dimerArrowR-HSA-8858369 (Reactome)
ACVRL1R-HSA-8858369 (Reactome)
ADPArrowR-HSA-201443 (Reactome)
ADPArrowR-HSA-201476 (Reactome)
AMH dimer:AMHR2 dimerArrowR-HSA-8858346 (Reactome)
AMH dimerR-HSA-8858346 (Reactome)
AMHR2 dimerR-HSA-8858346 (Reactome)
ATPR-HSA-201443 (Reactome)
ATPR-HSA-201476 (Reactome)
BMP2 dimerR-HSA-201457 (Reactome)
BMP2 dimerR-HSA-201810 (Reactome)

type II

receptor:Phospho-BMP type I receptor:I-SMAD
ArrowR-HSA-201475 (Reactome)
BMP:BMPRII:BMPRIArrowR-HSA-201457 (Reactome)
BMP:BMPRII:BMPRIR-HSA-201443 (Reactome)
BMP:BMPRII:BMPRImim-catalysisR-HSA-201443 (Reactome)
BMP:BMPRII:p-4S-BMPRIArrowR-HSA-201443 (Reactome)
BMP:BMPRII:p-4S-BMPRIR-HSA-201475 (Reactome)
BMP:BMPRII:p-4S-BMPRIR-HSA-201648 (Reactome)
BMP:BMPRII:p-4S-BMPRIR-HSA-201821 (Reactome)
BMP:p-BMPR:Endofin:SMAD1/5/8ArrowR-HSA-201648 (Reactome)
BMP:p-BMPR:Endofin:SMAD1/5/8R-HSA-201476 (Reactome)
BMP:p-BMPR:Endofin:SMAD1/5/8mim-catalysisR-HSA-201476 (Reactome)
BMP:p-BMPR:Endofin:p-2S-SMAD1/5/8ArrowR-HSA-201476 (Reactome)
BMP:p-BMPR:Endofin:p-2S-SMAD1/5/8R-HSA-201453 (Reactome)
BMP:p-BMPR:EndofinArrowR-HSA-201453 (Reactome)
BMP:p-BMPR:I-SMAD:SMURFArrowR-HSA-201821 (Reactome)
BMPRI dimerR-HSA-202604 (Reactome)
BMPRII dimerR-HSA-202604 (Reactome)
BMPRII:BMPRIArrowR-HSA-202604 (Reactome)
BMPRII:BMPRIR-HSA-201457 (Reactome)
GDF2 dimer, BMP10 dimerR-HSA-8858369 (Reactome)
I-SMAD:SMURFR-HSA-201821 (Reactome)
I-SMAD:p-2S-SMAD1/5/8ArrowR-HSA-202626 (Reactome)
I-SMADR-HSA-201475 (Reactome)
I-SMADR-HSA-202626 (Reactome)
Ligand Trap:BMP2ArrowR-HSA-201810 (Reactome)
Ligand TrapR-HSA-201810 (Reactome)
Nuclear ubiquitin ligasemim-catalysisR-HSA-201425 (Reactome)
R-HSA-201422 (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).
R-HSA-201423 (Reactome) SKI 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.
R-HSA-201425 (Reactome) The nuclear R-SMAD:Co-SMAD complex recruits ubiquitin conjugating enzymes, such as UBE2D1 and UBE2D3, that ubiquitinate the complex and eventually lead to its proteasomal degradation. This provides an end point to the signaling pathway.
R-HSA-201443 (Reactome) Formation of the hetero-tetrameric BMP2:receptor complex induces receptor rotation, so that their 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 of the type I receptor. It is not known if exactly 8 ATPs are required for the phosphorylation of type I receptor, there could be more or less than this number.
R-HSA-201445 (Reactome) SMAD2 is polyubiquitinated by SMURF2 and targeted for proteasome-mediated degradation.
R-HSA-201453 (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 ZFYVE9 (SARA). As a result, the phosphorylated R-SMAD dissociates from the activated receptor complex (TGFBR).
R-HSA-201457 (Reactome) The mature dimeric BMP2 binds with high affinity to its signalling receptor, the type II receptor serine/threonine kinase. The type II receptor is known to form dimeric complexes even in the absence of BMP2 (Rosenzweig et al.1995).
R-HSA-201472 (Reactome) The phosphorylated-r-SMAD1/5/8:Co-SMAD complex rapidly translocates to the nucleus where it binds directly to DNA and interacts with a plethora of transcription co-factors. Regulation of target gene expression can be either positive or negative. A classic example of a target gene of the pathway are the genes encoding for i-SMADs. Thus, BMP2/SMAD signalling induces the expression of the negative regulators of the pathway (a negative feedback loop).
R-HSA-201475 (Reactome) I-SMADs reside in the nucleus presumably to be sequestered from the BMP2:receptor complex and thus avoid inappropriate silencing of the signalling pathway. Upon activation of the signalling pathway, I-SMADs exit the nucleus and are recruited to the signalling BMP2: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.
R-HSA-201476 (Reactome) Activated type I receptor kinase directly phosphorylates two of the C-terminal serine residues of SMAD1, SMAD5 or SMAD8. Binding of these R-SMADs to the L45 loop of the type I receptor is critical for this event.
R-HSA-201648 (Reactome) Endofin 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.
R-HSA-201810 (Reactome) BMP ligand traps are cystine-knot containing proteins which bind BMPs and antagonise their actions. They are active during organ development and morphogenesis. Different BMP ligand traps show specific spatio-temporal expression during development, and selective activity against specific BMP ligands.
R-HSA-201821 (Reactome) Smad6 and Smad7, the two I-Smads, bind directly to the BMP type I receptors and recruit the ubiquitin ligase Smurf1. This reaction leads to competitive inhibition of R-Smad binding to the type I receptor and activating phosphorylation by the receptor, and also leads to BMP receptor ubiquitination and degradation.
R-HSA-202604 (Reactome) BMP receptors, unlike TGF-beta receptors are known to form hetero-oligomeric complexes in the endoplasmic reticulum and are transported as oligomers to the plasma membrane where they bind ligand. However, evidence for ligand-induced heteromeric BMP receptor complexes on the cell surface has also been published, leading to a model where both pre-formed and ligand-induced receptor oligomers are encountered on the plasma membrane. Based on the latter, a theory has been formulated that suggests that the signaling outcome from pre-formed and ligand-induced BMP receptor complexes is different. The mechanism that might explain this theory must involve different ways of internalization and trafficking of the BMP receptor complexes.
R-HSA-202626 (Reactome) I-SMAD selectively antagonizes BMP-activated Smad1/5/9 by acting as a CO-SMAD decoy.
R-HSA-8858346 (Reactome) Anti-Müllerian hormone (AMH), also known as Müllerian inhibiting substance (MIS), is a member of the Transforming growth factor Beta (TGFB) superfamily (Massagué 1998). It plays a crucial role during male sexual differentiation, inducing the regression of the Müllerian ducts in male fetuses (Nef & Parada 2000). Mutations in the AMH gene (Cate et al.1986) cause Persistent Müllerian duct syndrome, a rare form of male pseudohermaphroditism (Belville et al. 1999, MacLaughlin & Donahoe 2004). As a member of the TGFB superfamily, it was expected that AMH signaling would resemble the signaling pathways defined for other family members (Visser 2003). TGFB family members signal through a heteromeric receptor complex consisting of two related serine/threonine kinase receptors, the type I and II receptors. The dimeric ligand initially binds to the type II receptor, which recruits and phosphorylates the type I receptor. This activates the type I receptor resulting in phosphorylation of Smad proteins.

Prior to secretion, AMH undergoes glycosylation and dimerization to produce a 144-kDa dimer composed of identical disulphide-linked 72-kDa monomer subunits; each monomer contains an N-terminal domain 'pro' region and a C-terminal domain 'mature' region. The type II receptor for AMH is AMHR2 (Baarends et al. 1994, di Clemente et al. 1994, Teixeira et al. 1996). AMH must be cleaved to bind AMHR2 but dissociation of the pro-region from the mature C-terminal dimer is not required for this initial interaction (di Clemente et al. 2010). The AMH:AMHR2 complex has been reported to recruit in a context specific manner two candidate type I receptors, Bone morphogenetic protein receptor type-1B (BMPR1A, ALK3) (Jamin et al. 2002), and Activin receptor type-1 (ACVR1, ALK2) (Clarke et al. 2001, Visser et al. 2001) leading to SMAD1/5/8 activation (Gouedard et al. 2000, Zhan et al. 2006).
R-HSA-8858369 (Reactome) Growth/differentiation factor 2 (Bone morphogenic protein 9, BMP9, GDF2) and Bone morphogenetic protein 10 (BMP10) bind with sub-nanomolar affinities to both the type I receptor Serine/threonine-protein kinase receptor R3 (ACVRL1, Activin receptor-like kinase 1, ALK1) and the type II receptor Activin receptor type-2B (ActR-IIB, ACVR2B) (Scharpfenecker et al. 2007, Laurent et al. 2007, Townson et al. 2012). BMP9 also bind with high affinity the type II receptors Bone morphogenetic protein receptor type-2 (BMPR2) and Activin receptor type-2A (ACVR2A, ActRIIA) (Kuo et al. 2014; Kienast et al. 2016). BMP9 binding leads to phosphorylation of Mothers against decapentaplegic homolog 1 (SMAD1), SMAD5 and SMAD8 in microvascular endothelial cells (David et al. 2007).

ACVRL1 is an important regulator of normal blood vessel development as well as pathological tumor angiogenesis (Massague 1998).
SKIR-HSA-201423 (Reactome)
SMAD1/5/8R-HSA-201445 (Reactome)
SMAD1/5/8R-HSA-201648 (Reactome)
SMAD4R-HSA-201422 (Reactome)
SMURFmim-catalysisR-HSA-201445 (Reactome)
ZFYVE16R-HSA-201648 (Reactome)
p-2S-SMAD1/5/8:SMAD4:SKIArrowR-HSA-201423 (Reactome)
p-2S-SMAD1/5/8:SMAD4ArrowR-HSA-201422 (Reactome)
p-2S-SMAD1/5/8:SMAD4ArrowR-HSA-201472 (Reactome)
p-2S-SMAD1/5/8:SMAD4R-HSA-201423 (Reactome)
p-2S-SMAD1/5/8:SMAD4R-HSA-201425 (Reactome)
p-2S-SMAD1/5/8:SMAD4R-HSA-201472 (Reactome)
p-2S-SMAD1/5/8ArrowR-HSA-201453 (Reactome)
p-2S-SMAD1/5/8R-HSA-201422 (Reactome)
p-2S-SMAD1/5/8R-HSA-202626 (Reactome)
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