Signaling by BMP (Homo sapiens)
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Description
The TGF-beta/BMP (bone morphogenetic protein) pathway incorporates several signalling pathways that share most, but not all, components of a central signal transduction engine. The general signalling scheme is rather simple: upon binding of a ligand, an activated plasma membrane receptor complex is formed, which passes on the signal towards the nucleus through a phosphorylated receptor-activated SMAD (r-SMAD). In the nucleus, the activated r-SMAD promotes transcription in a complex with a closely-related helper molecule termed the Co-SMAD. However, this simple linear pathway expands into a network when various regulatory components and mechanisms are taken into account. The signalling pathway includes a great variety of different TGF-beta/BMP superfamily ligands and receptors, several types of the r-SMAD, and functionally critical negative feedback loops. The r-SMAD/Co-SMAD can interact with a great number of transcriptional co-activators/co-repressors to regulate positively or negatively effector genes, so that the interpretation of a signal depends on the cell-type and cross talk with other signalling pathways such as Notch, MAPK and Wnt. The pathway plays a number of different biological roles in the control of embryonic and adult cell proliferation and differentiation, and it is implicated in a great number of human diseases.
Source:Reactome.
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- Scharpfenecker M, van Dinther M, Liu Z, van Bezooijen RL, Zhao Q, Pukac L, Löwik CW, ten Dijke P.; ''BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis.''; PubMed Europe PMC Scholia
- Xiao Z, Watson N, Rodriguez C, Lodish HF.; ''Nucleocytoplasmic shuttling of Smad1 conferred by its nuclear localization and nuclear export signals.''; PubMed Europe PMC Scholia
- Hoodless PA, Haerry T, Abdollah S, Stapleton M, O'Connor MB, Attisano L, Wrana JL.; ''MADR1, a MAD-related protein that functions in BMP2 signaling pathways.''; PubMed Europe PMC Scholia
- 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
- 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
- Allendorph GP, Vale WW, Choe S.; ''Structure of the ternary signaling complex of a TGF-beta superfamily member.''; PubMed Europe PMC Scholia
- Goumans MJ, Zwijsen A, Ten Dijke P, Bailly S.; ''Bone Morphogenetic Proteins in Vascular Homeostasis and Disease.''; PubMed Europe PMC Scholia
- Miyazono K, Kamiya Y, Morikawa M.; ''Bone morphogenetic protein receptors and signal transduction.''; PubMed Europe PMC Scholia
- Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P, Heldin CH, Miyazono K.; ''Cloning and characterization of a human type II receptor for bone morphogenetic proteins.''; PubMed Europe PMC Scholia
- Qin BY, Chacko BM, Lam SS, de Caestecker MP, Correia JJ, Lin K.; ''Structural basis of Smad1 activation by receptor kinase phosphorylation.''; PubMed Europe PMC Scholia
- Gazzerro E, Canalis E.; ''Bone morphogenetic proteins and their antagonists.''; PubMed Europe PMC Scholia
- Tajima Y, Goto K, Yoshida M, Shinomiya K, Sekimoto T, Yoneda Y, Miyazono K, Imamura T.; ''Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-beta signaling by Smad7.''; PubMed Europe PMC Scholia
- Suzuki C, Murakami G, Fukuchi M, Shimanuki T, Shikauchi Y, Imamura T, Miyazono K.; ''Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane.''; PubMed Europe PMC Scholia
- Wang W, Mariani FV, Harland RM, Luo K.; ''Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells.''; PubMed Europe PMC Scholia
- 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
- 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
- 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
- Baarends WM, van Helmond MJ, Post M, van der Schoot PJ, Hoogerbrugge JW, de Winter JP, Uilenbroek JT, Karels B, Wilming LG, Meijers JH.; ''A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the müllerian duct.''; PubMed Europe PMC Scholia
- Lagna G, Hata A, Hemmati-Brivanlou A, Massagué J.; ''Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways.''; PubMed Europe PMC Scholia
- Gruendler C, Lin Y, Farley J, Wang T.; ''Proteasomal degradation of Smad1 induced by bone morphogenetic proteins.''; PubMed Europe PMC Scholia
- David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S.; ''Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells.''; PubMed Europe PMC Scholia
- Heldin CH, ten Dijke P.; ''SMAD destruction turns off signalling.''; PubMed Europe PMC Scholia
- 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
- 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
- Nohe A, Hassel S, Ehrlich M, Neubauer F, Sebald W, Henis YI, Knaus P.; ''The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways.''; PubMed Europe PMC Scholia
- Shi W, Chang C, Nie S, Xie S, Wan M, Cao X.; ''Endofin acts as a Smad anchor for receptor activation in BMP signaling.''; PubMed Europe PMC Scholia
- 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
- Xiao Z, Brownawell AM, Macara IG, Lodish HF.; ''A novel nuclear export signal in Smad1 is essential for its signaling activity.''; PubMed Europe PMC Scholia
- Murakami G, Watabe T, Takaoka K, Miyazono K, Imamura T.; ''Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads.''; PubMed Europe PMC Scholia
- 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
- Gilboa L, Nohe A, Geissendörfer T, Sebald W, Henis YI, Knaus P.; ''Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors.''; PubMed Europe PMC Scholia
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADP | Arrow | R-HSA-201443 (Reactome)  | ||
| ADP | Arrow | R-HSA-201476 (Reactome) | ||
| ATP | R-HSA-201443 (Reactome) | |||
| ATP | R-HSA-201476 (Reactome) | |||
| BMP2:BMP
type II receptor:Phospho-BMP type I receptor:I-SMAD | Arrow | R-HSA-201475 (Reactome) | ||
| BMP:BMPRII:BMPRI | Arrow | R-HSA-201457 (Reactome) | ||
| BMP:BMPRII:BMPRI | R-HSA-201443 (Reactome) | |||
| BMP:BMPRII:BMPRI | mim-catalysis | R-HSA-201443 (Reactome) | ||
| BMP:BMPRII:p-4S-BMPRI | Arrow | R-HSA-201443 (Reactome) | ||
| BMP:BMPRII:p-4S-BMPRI | R-HSA-201475 (Reactome) | |||
| BMP:BMPRII:p-4S-BMPRI | R-HSA-201648 (Reactome) | |||
| BMP:BMPRII:p-4S-BMPRI | R-HSA-201821 (Reactome) | |||
| BMP:BMPRII:p-4S-BMPRI | mim-catalysis | R-HSA-201476 (Reactome) | ||
| BMP:p-BMPR:Endofin:SMAD1/5/8 | Arrow | R-HSA-201648 (Reactome) | ||
| BMP:p-BMPR:Endofin:SMAD1/5/8 | R-HSA-201476 (Reactome) | |||
| BMP:p-BMPR:Endofin:p-2S-SMAD1/5/8 | Arrow | R-HSA-201476 (Reactome) | ||
| BMP:p-BMPR:Endofin:p-2S-SMAD1/5/8 | R-HSA-201453 (Reactome) | |||
| BMP:p-BMPR:Endofin | Arrow | R-HSA-201453 (Reactome) | ||
| BMP:p-BMPR:I-SMAD:SMURF | Arrow | R-HSA-201821 (Reactome) | ||
| BMPRI dimer | R-HSA-202604 (Reactome) | |||
| BMPRII dimer | R-HSA-202604 (Reactome) | |||
| BMPRII:BMPRI | Arrow | R-HSA-202604 (Reactome) | ||
| BMPRII:BMPRI | R-HSA-201457 (Reactome) | |||
| Dimeric BMP2 | R-HSA-201457 (Reactome) | |||
| Dimeric BMP2 | R-HSA-201810 (Reactome) | |||
| Dimeric BMP2 | mim-catalysis | R-HSA-201457 (Reactome) | ||
| I-SMAD:SMURF | R-HSA-201821 (Reactome) | |||
| I-SMAD:p-2S-SMAD1/5/8 | Arrow | R-HSA-202626 (Reactome) | ||
| I-SMAD | R-HSA-201475 (Reactome) | |||
| I-SMAD | R-HSA-202626 (Reactome) | |||
| Ligand Trap:BMP2 | Arrow | R-HSA-201810 (Reactome) | ||
| Ligand Trap | R-HSA-201810 (Reactome) | |||
| Nuclear ubiquitin ligase | mim-catalysis | R-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. | |||
| 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 SMAD2 or SMAD3. 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. | |||
| SKI | R-HSA-201423 (Reactome) | |||
| SMAD1/5/8 | R-HSA-201445 (Reactome) | |||
| SMAD1/5/8 | R-HSA-201648 (Reactome) | |||
| SMAD4 | R-HSA-201422 (Reactome) | |||
| SMURF | mim-catalysis | R-HSA-201445 (Reactome) | ||
| ZFYVE16 | R-HSA-201648 (Reactome) | |||
| p-2S-SMAD1/5/8:SMAD4:SKI | Arrow | R-HSA-201423 (Reactome) | ||
| p-2S-SMAD1/5/8:SMAD4 | Arrow | R-HSA-201422 (Reactome) | ||
| p-2S-SMAD1/5/8:SMAD4 | Arrow | R-HSA-201472 (Reactome) | ||
| p-2S-SMAD1/5/8:SMAD4 | R-HSA-201423 (Reactome) | |||
| p-2S-SMAD1/5/8:SMAD4 | R-HSA-201425 (Reactome) | |||
| p-2S-SMAD1/5/8:SMAD4 | R-HSA-201472 (Reactome) | |||
| p-2S-SMAD1/5/8 | Arrow | R-HSA-201453 (Reactome) | ||
| p-2S-SMAD1/5/8 | R-HSA-201422 (Reactome) | |||
| p-2S-SMAD1/5/8 | R-HSA-202626 (Reactome) |
