smad5 protein


Summary: A receptor-regulated smad protein that undergoes PHOSPHORYLATION by BONE MORPHOGENETIC PROTEIN RECEPTORS. It regulates BONE MORPHOGENETIC PROTEIN signaling and is essential for PHYSIOLOGICAL ANGIOGENESIS.

Top Publications

  1. Fei T, Xia K, Li Z, Zhou B, Zhu S, Chen H, et al. Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination. Genome Res. 2010;20:36-44 pubmed publisher
    ..Combined with computational analysis, our results suggest that SMAD-mediated BMP signaling balances self-renewal versus differentiation by modulating a set of developmental regulators. ..
  2. Fujii M, Takeda K, Imamura T, Aoki H, Sampath T, Enomoto S, et al. Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Mol Biol Cell. 1999;10:3801-13 pubmed
    ..Osteoblast differentiation induced by BMPs is thus mediated mainly via the Smad-signaling pathway, whereas chondrogenic differentiation may be transmitted by Smad-dependent and independent pathways. ..
  3. Zaidi S, Sullivan A, Van Wijnen A, Stein J, Stein G, Lian J. Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites. Proc Natl Acad Sci U S A. 2002;99:8048-53 pubmed
    ..Thus, Runx-mediated intranuclear targeting of Smads is critical for the integration of two distinct pathways essential for fetal development. ..
  4. Zwijsen A, van Grunsven L, Bosman E, Collart C, Nelles L, Umans L, et al. Transforming growth factor beta signalling in vitro and in vivo: activin ligand-receptor interaction, Smad5 in vasculogenesis, and repression of target genes by the deltaEF1/ZEB-related SIP1 in the vertebrate embryo. Mol Cell Endocrinol. 2001;180:13-24 pubmed
    ..We conclude with a summary of our results with a Smad-interacting transcriptional repressor but focus on its biological significance in the vertebrate embryo. ..
  5. Goumans M, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C, et al. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell. 2003;12:817-28 pubmed
    ..TGFbeta type II receptor is also required for ALK1 activation by TGFbeta. Interestingly, ALK1 not only induces a biological response opposite to that of ALK5 but also directly antagonizes ALK5/Smad signaling. ..
  6. Tanikawa R, Tanikawa T, Hirashima M, Yamauchi A, Tanaka Y. Galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway. Biochem Biophys Res Commun. 2010;394:317-22 pubmed publisher
    ..Because Smad1 is phosphorylated by BMP receptors, we propose that formation of the CD44/BMP receptor complex induced by galectin-9 may provide a trigger for the activation of Smads. ..
  7. Liu I, Schilling S, Knouse K, Choy L, Derynck R, Wang X. TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch. EMBO J. 2009;28:88-98 pubmed publisher
  8. David L, Mallet C, Mazerbourg S, Feige J, Bailly S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood. 2007;109:1953-61 pubmed
    ..Taken together, our results suggest that BMP9 and BMP10 are two specific ALK1 ligands that may physiologically trigger the effects of ALK1 on angiogenesis. ..
  9. Arnold S, Maretto S, Islam A, Bikoff E, Robertson E. Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo. Dev Biol. 2006;296:104-18 pubmed
    ..These experiments demonstrate for the first time that Smad1 and Smad5 function cooperatively to govern BMP target gene expression in the early mammalian embryo. ..

More Information


  1. Afzal F, Pratap J, Ito K, Ito Y, Stein J, Van Wijnen A, et al. Smad function and intranuclear targeting share a Runx2 motif required for osteogenic lineage induction and BMP2 responsive transcription. J Cell Physiol. 2005;204:63-72 pubmed
    ..Our findings suggest that TGFbeta/ BMP2 signaling, MAPK dependent phosphorylation, and Runx2 subnuclear targeting converge to induce the osteogenic phenotype. ..
  2. Vrljicak P, Myburgh D, Ryan A, Van Rooijen M, Mummery C, Gupta I. Smad expression during kidney development. Am J Physiol Renal Physiol. 2004;286:F625-33 pubmed
    ..Based on the observed patterns of expression, we speculate that individual or combinations of Smads may play specific roles in cell-fate determination during kidney development. ..
  3. Cho Y, Kim W, Yoon W, Woo K, Baek J, Lee G, et al. Wnt3a stimulates Mepe, matrix extracellular phosphoglycoprotein, expression directly by the activation of the canonical Wnt signaling pathway and indirectly through the stimulation of autocrine Bmp-2 expression. J Cell Physiol. 2012;227:2287-96 pubmed publisher
    ..Collectively, Wnt3a stimulates Mepe transcription directly by a canonical Wnt signaling pathway through ?-catenin and Lef-1 and indirectly through the activation of a Bmp-2 autocrine loop. ..
  4. Lele Z, Bakkers J, Hammerschmidt M. Morpholino phenocopies of the swirl, snailhouse, somitabun, minifin, silberblick, and pipetail mutations. Genesis. 2001;30:190-4 pubmed
  5. Chang H, Huylebroeck D, Verschueren K, Guo Q, Matzuk M, Zwijsen A. Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development. 1999;126:1631-42 pubmed
    ..Despite the expression of Smad5 from gastrulation onwards, and in contrast to knockouts of Smad2 and Smad4, Smad5 only becomes essential later in extraembryonic and embryonic development. ..
  6. Oh S, Seki T, Goss K, Imamura T, Yi Y, Donahoe P, et al. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A. 2000;97:2626-31 pubmed
    ..Taken together, our results suggest that the balance between the ALK1 and ALK5 signaling pathways in endothelial cells plays a crucial role in determining vascular endothelial properties during angiogenesis. ..
  7. Hild M, Dick A, Rauch G, Meier A, Bouwmeester T, Haffter P, et al. The smad5 mutation somitabun blocks Bmp2b signaling during early dorsoventral patterning of the zebrafish embryo. Development. 1999;126:2149-59 pubmed
    ..and zygotic effect of the sbntc24 mutation is caused by a change in a single amino acid in the L3 loop of Smad5 protein which transforms Smad5 into an antimorphic version, inhibiting wild-type Smad5 and related Smad proteins...
  8. Wang S, De Caestecker M, Kopp J, Mitu G, LaPage J, Hirschberg R. Renal bone morphogenetic protein-7 protects against diabetic nephropathy. J Am Soc Nephrol. 2006;17:2504-12 pubmed
    ..The findings also establish a role for endogenous glomerular BMP-7 as an autocrine regulator of podocyte integrity in vivo. ..
  9. Chang S, Chang C, Lee D, Lee P, Yeh Y, Yeh C, et al. Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad. Proc Natl Acad Sci U S A. 2008;105:3927-32 pubmed publisher
  10. Rios I, Alvarez Rodriguez R, Marti E, Pons S. Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through Smad5 signalling. Development. 2004;131:3159-68 pubmed
    ..We propose a model in which Bmp2-mediated Smad5 signalling suppresses the proliferative response to Shh by downregulation of the pathway, and allows granule cell precursor to enter their differentiation programme. ..
  11. Retting K, Song B, Yoon B, Lyons K. BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development. 2009;136:1093-104 pubmed publisher
    ..Finally, we tested whether FGF exerts its antagonistic effects directly through Smad linker phosphorylation. The results support the alternative conclusion that the effects of FGFs on BMP signaling are indirect in vivo. ..
  12. Yang X, Castilla L, Xu X, Li C, Gotay J, Weinstein M, et al. Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Development. 1999;126:1571-80 pubmed
    ..These data suggest that SMAD5 may regulate endothelium-mesenchyme interactions during angiogenesis and that it is essential for mesenchymal survival. ..
  13. Macias Silva M, Hoodless P, Tang S, Buchwald M, Wrana J. Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem. 1998;273:25628-36 pubmed
    ..Furthermore, we show that ALK1 (TSRI), an orphan receptor that is closely related to ALK2 also mediates Smad1 signaling. Thus, ALK1 and ALK2 induce Smad1-dependent pathways and ALK2 functions to mediate BMP7 but not activin signaling. ..
  14. Aoki H, Fujii M, Imamura T, Yagi K, Takehara K, Kato M, et al. Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction. J Cell Sci. 2001;114:1483-9 pubmed
    ..Thus, ALK-2 and ALK-3 (or ALK-6) might synergistically induce osteoblast differentiation of C2C12 cells, possibly through efficient activation of downstream signaling pathways. ..
  15. Goumans M, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, Ten Dijke P. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 2002;21:1743-53 pubmed
    ..Our results suggest that TGF-beta regulates the activation state of the endothelium via a fine balance between ALK5 and ALK1 signalling. ..
  16. Orvis G, Jamin S, Kwan K, Mishina Y, Kaartinen V, Huang S, et al. Functional redundancy of TGF-beta family type I receptors and receptor-Smads in mediating anti-Mullerian hormone-induced Mullerian duct regression in the mouse. Biol Reprod. 2008;78:994-1001 pubmed publisher
    ..Loss of these genes in the Müllerian duct mesenchyme results in male infertility due to retention of Müllerian duct derivatives in an otherwise virilized male. ..
  17. Moustakas A, Souchelnytskyi S, Heldin C. Smad regulation in TGF-beta signal transduction. J Cell Sci. 2001;114:4359-69 pubmed
    ..Finally, the inhibitory Smads (I-Smads) block phosphorylation of R-Smads by the receptors and promote ubiquitination and degradation of receptor complexes, thus inhibiting signalling. ..
  18. Pangas S, Li X, Umans L, Zwijsen A, Huylebroeck D, Gutierrez C, et al. Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice. Mol Cell Biol. 2008;28:248-57 pubmed
    ..These data strongly implicate the BR-SMADs as part of a critical developmental pathway in ovaries and testis that, when disrupted, leads to malignant transformation...
  19. McReynolds L, Gupta S, Figueroa M, Mullins M, Evans T. Smad1 and Smad5 differentially regulate embryonic hematopoiesis. Blood. 2007;110:3881-90 pubmed
    ..Our results suggest that specificity of BMP signaling output, with respect to hematopoiesis, can be explained by differential functions of Smad1 and Smad5. ..
  20. Rath B, Nam J, Deschner J, Schaumburger J, Tingart M, Grassel S, et al. Biomechanical forces exert anabolic effects on osteoblasts by activation of SMAD 1/5/8 through type 1 BMP receptor. Biorheology. 2011;48:37-48 pubmed publisher
    ..Collectively, the present findings demonstrate that biomechanical stimulation of osteoblasts activates SMAD 1/5/8 in the BMP signaling pathway through BMPR1 and may enhance osteogenesis by upregulating SMAD-dependent osteogenic genes. ..
  21. Fukuda T, Kohda M, Kanomata K, Nojima J, Nakamura A, Kamizono J, et al. Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva. J Biol Chem. 2009;284:7149-56 pubmed publisher
    ..Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP...
  22. Rath B, Nam J, Knobloch T, Lannutti J, Agarwal S. Compressive forces induce osteogenic gene expression in calvarial osteoblasts. J Biomech. 2008;41:1095-103 pubmed publisher
  23. Leboy P, Grasso Knight G, D ANGELO M, Volk S, Lian J, Drissi H, et al. Smad-Runx interactions during chondrocyte maturation. J Bone Joint Surg Am. 2001;83-A Suppl 1:S15-22 pubmed
    ..These studies demonstrate that both BMP-activated Smads and Runx2 levels can modulate chondrocyte transition to hypertrophy. ..
  24. Oxburgh L, Robertson E. Dynamic regulation of Smad expression during mesenchyme to epithelium transition in the metanephric kidney. Mech Dev. 2002;112:207-11 pubmed
    ..Down-regulation is complete in lithium chloride induced mesenchymal condensates, indicating that Smad regulation takes place at an early stage, prior to mesenchyme to epithelium transition. ..
  25. Dick A, Meier A, Hammerschmidt M. Smad1 and Smad5 have distinct roles during dorsoventral patterning of the zebrafish embryo. Dev Dyn. 1999;216:285-98 pubmed
  26. Monteiro R, de Sousa Lopes S, Korchynskyi O, Ten Dijke P, Mummery C. Spatio-temporal activation of Smad1 and Smad5 in vivo: monitoring transcriptional activity of Smad proteins. J Cell Sci. 2004;117:4653-63 pubmed
    ..We have thus generated, for the first time, an in vivo readout for studying the role of Smad1/5-mediated transcriptional activity in development. ..
  27. Weinstein M, Yang X, Deng C. Functions of mammalian Smad genes as revealed by targeted gene disruption in mice. Cytokine Growth Factor Rev. 2000;11:49-58 pubmed
    ..Combinatorial genetics has also revealed functions of Smads in left/right isomerism and liver development. ..
  28. Valdimarsdottir G, Goumans M, Rosendahl A, Brugman M, Itoh S, Lebrin F, et al. Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation. 2002;106:2263-70 pubmed
    ..Id1 expression is strongly induced by BMP in ECs. Ectopic expression of Id1 induces EC migration and tube formation. Moreover, Id1 played a critical role in mediating BMP-induced EC migration. ..
  29. Faure S, Lee M, Keller T, ten Dijke P, Whitman M. Endogenous patterns of TGFbeta superfamily signaling during early Xenopus development. Development. 2000;127:2917-31 pubmed
    ..We discuss the implications of our results for endogenous functions of BMP and activin-like signals as candidate morphogens regulating primary germ layer formation and dorsoventral patterning of the early Xenopus embryo. ..
  30. Nohe A, Hassel S, Ehrlich M, Neubauer F, Sebald W, Henis Y, et al. The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem. 2002;277:5330-8 pubmed
  31. Wang L, Zhang X, Guo Y, Chen X, Li R, Liu L, et al. Involvement of BMPs/Smad signaling pathway in mechanical response in osteoblasts. Cell Physiol Biochem. 2010;26:1093-102 pubmed publisher
    ..Mechanical strain might promote osteoblasts differentiation through BMPs/Smad signaling pathway. The strain causes a drop in Smurf1 levels, leading to accumulation of Smad proteins and, subsequently, to enhanced BMPs/Smad signaling. ..
  32. Nguyen T, Roestenberg P, van Nieuwenhoven F, Bovenschen N, Li Z, Xu L, et al. CTGF inhibits BMP-7 signaling in diabetic nephropathy. J Am Soc Nephrol. 2008;19:2098-107 pubmed publisher
  33. Ascenzi M, Blanco C, Drayer I, Kim H, Wilson R, Retting K, et al. Effect of localization, length and orientation of chondrocytic primary cilium on murine growth plate organization. J Theor Biol. 2011;285:147-55 pubmed publisher
    ..Our mathematically predicted cell division process will need to be observed experimentally to advance the identification of ciliary function in the growth plate...
  34. Morikawa M, Koinuma D, Tsutsumi S, Vasilaki E, Kanki Y, Heldin C, et al. ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif. Nucleic Acids Res. 2011;39:8712-27 pubmed publisher
    ..These results provide insights into the molecular mechanism of BMP signaling and the pathogenesis of vascular lesions of certain genetic disorders, including hereditary hemorrhagic telangiectasia...
  35. Aoyama M, Sun Wada G, Yamamoto A, Yamamoto M, Hamada H, Wada Y. Spatial restriction of bone morphogenetic protein signaling in mouse gastrula through the mVam2-dependent endocytic pathway. Dev Cell. 2012;22:1163-75 pubmed publisher
    ..We found that mVam2, which interacts with BMP type I receptor, is required for the spatiotemporal modulation of BMP signaling, via sequestration of the receptor complex in the late stages of the endocytic pathway...
  36. Osório C, Chacón P, Kisiswa L, White M, Wyatt S, Rodríguez Tébar A, et al. Growth differentiation factor 5 is a key physiological regulator of dendrite growth during development. Development. 2013;140:4751-62 pubmed publisher
  37. Liu Y, Sun R, Lin X, Liang D, Deng Q, Lan K. Kaposi's sarcoma-associated herpesvirus-encoded microRNA miR-K12-11 attenuates transforming growth factor beta signaling through suppression of SMAD5. J Virol. 2012;86:1372-81 pubmed publisher
  38. Zavadil J, Svoboda P, Liang H, Kottickal L, Nagarajan L. An antisense transcript to SMAD5 expressed in fetal and tumor tissues. Biochem Biophys Res Commun. 1999;255:668-72 pubmed
    ..The findings raise the possibility that DAMS may be a fail-safe mechanism for precise regulation of SMAD5 transcript levels that may be critical in maintaining normal homeostasis. ..
  39. Gonzalez C, Gonzalez B, Rulli S, Dos Santos M, Mattos Jardim Costa G, Franca L, et al. TGF-beta1 system in Leydig cells. Part II: TGF-beta1 and progesterone, through Smad1/5, are involved in the hyperplasia/hypertrophy of Leydig cells. J Reprod Dev. 2010;56:400-4 pubmed
    ..Thus, it turned out that the administration of progesterone and TGF-beta1 augmented the volume of Leydig cells. These results indicate a clear effect of TGF-beta1 in the hypertrophy/hyperplasia of Leydig cells...
  40. Eivers E, Demagny H, De Robertis E. Integration of BMP and Wnt signaling via vertebrate Smad1/5/8 and Drosophila Mad. Cytokine Growth Factor Rev. 2009;20:357-65 pubmed publisher
    ..We summarize here the significance of linker-phosphorylated Smad1/Mad in relation to signal intensity and duration, and how this integrates the Wnt and BMP pathways during cell differentiation. ..
  41. Singhatanadgit W, Salih V, Olsen I. Shedding of a soluble form of BMP receptor-IB controls bone cell responses to BMP. Bone. 2006;39:1008-1017 pubmed publisher
    ..In conclusion, our study has provided evidence, for the first time, that BMPR can be modulated at the cell surface by the shedding of a soluble form of the antigen, resulting in a markedly diminished response to BMP-2 in vitro. ..
  42. Roman B, Pham V, Lawson N, Kulik M, Childs S, Lekven A, et al. Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development. 2002;129:3009-19 pubmed
    ..Movies available on-line ..
  43. Gupta A, Cao W, Chellaiah M. Integrin ?v?3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-?B ligand signaling axis. Mol Cancer. 2012;11:66 pubmed publisher
    ..These observations imply a novel mechanistic insight into the role of these proteins in bone loss associated with bone metastases in patients with prostate cancer. ..
  44. Jiang D, Aguiar R. MicroRNA-155 controls RB phosphorylation in normal and malignant B lymphocytes via the noncanonical TGF-?1/SMAD5 signaling module. Blood. 2014;123:86-93 pubmed publisher
  45. Ho C, Zhou X, Mishina Y, Bernard D. Mechanisms of bone morphogenetic protein 2 (BMP2) stimulated inhibitor of DNA binding 3 (Id3) transcription. Mol Cell Endocrinol. 2011;332:242-52 pubmed publisher
    ..Collectively, we have defined a general mechanism whereby BMP2 regulates Id3/ID3 transcription in different cell types and in different species. ..
  46. Tao S, Sampath K. Alternative splicing of SMADs in differentiation and tissue homeostasis. Dev Growth Differ. 2010;52:335-42 pubmed publisher
    ..Here, we discuss the roles of various SMAD isoforms, and the consequences of mis-regulation of SMAD splicing in development and tissue homeostasis. ..
  47. Tian F, Zhou A, Smits A, Larsson E, Goumans M, Heldin C, et al. Endothelial cells are activated during hypoxia via endoglin/ALK-1/SMAD1/5 signaling in vivo and in vitro. Biochem Biophys Res Commun. 2010;392:283-8 pubmed publisher
    ..ENG/ALK-1 signaling is one of the factors that regulate endothelial cell activity during adaptive cardiac angiogenesis. ..
  48. Qin W, Yang F, Deng R, Li D, Song Z, Tian Y, et al. Smad 1/5 is involved in bone morphogenetic protein-2-induced odontoblastic differentiation in human dental pulp cells. J Endod. 2012;38:66-71 pubmed publisher
    ..However, the mechanism by which BMP-2 induces odontoblastic differentiation has not yet been established. In the present study, we examined the involvement of the BMP/Smad pathway in mediating odontoblastic differentiation in DPCs...
  49. Moya I, Umans L, Maas E, Pereira P, Beets K, Francis A, et al. Stalk cell phenotype depends on integration of Notch and Smad1/5 signaling cascades. Dev Cell. 2012;22:501-14 pubmed publisher
    ..Our findings provide in vivo evidence for a regulatory loop between BMP/TGFβ-Smad1/5 and Notch signaling that orchestrates tip- versus stalk-cell selection and vessel plasticity. ..
  50. Dick A, Hild M, Bauer H, Imai Y, Maifeld H, Schier A, et al. Essential role of Bmp7 (snailhouse) and its prodomain in dorsoventral patterning of the zebrafish embryo. Development. 2000;127:343-54 pubmed
    ..mRNA injection studies and double mutant analyses indicate that Bmp2b and Bmp7 closely cooperate and that Bmp2b/Bmp7 signaling is transduced by Smad5 and antagonized by Chordino. ..
  51. Giusti B, Margheri F, Rossi L, Lapini I, Magi A, Serratì S, et al. Desmoglein-2-integrin Beta-8 interaction regulates actin assembly in endothelial cells: deregulation in systemic sclerosis. PLoS ONE. 2013;8:e68117 pubmed publisher
    ..We have shown that impairment of actin assembly as a result of desmoglein-2/integrin-beta8 complex formation is a major factor contributing to angiogenesis deregulation in Systemic sclerosis. ..
  52. Maurya A, Tan H, Souren M, Wang X, Wittbrodt J, Ingham P. Integration of Hedgehog and BMP signalling by the engrailed2a gene in the zebrafish myotome. Development. 2011;138:755-65 pubmed publisher
  53. Hatakeyama Y, Nguyen J, Wang X, Nuckolls G, Shum L. Smad signaling in mesenchymal and chondroprogenitor cells. J Bone Joint Surg Am. 2003;85-A Suppl 3:13-8 pubmed
    ..However, in chondroprogenitor cells, BMP stimulates differentiation through mechanisms mediated by Smad1 or Smad5 in combination with Smad4. ..