type i activin receptors


Summary: One of the two types of ACTIVIN RECEPTORS or activin receptor-like kinases (ALK'S). There are several type I activin receptors. The major active ones are ALK-2 (ActR-IA) and ALK-4 (ActR-IB).

Top Publications

  1. Matyas G, Arnold E, Carrel T, Baumgartner D, Boileau C, Berger W, et al. Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. Hum Mutat. 2006;27:760-9 pubmed
  2. Watanabe K, Hamada S, Bianco C, Mancino M, Nagaoka T, Gonzales M, et al. Requirement of glycosylphosphatidylinositol anchor of Cripto-1 for trans activity as a Nodal co-receptor. J Biol Chem. 2007;282:35772-86 pubmed
    ..These observations suggest that GPI attachment of CR-1 is required for the paracrine activity as a Nodal co-receptor. ..
  3. Robinson P, Arteaga Solis E, Baldock C, Collod Beroud G, Booms P, De Paepe A, et al. The molecular genetics of Marfan syndrome and related disorders. J Med Genet. 2006;43:769-87 pubmed
    ..Mutations in FBN1 and other genes found in MFS and related disorders will be discussed, and novel concepts concerning the complex and multiple mechanisms of the pathogenesis of MFS will be explained...
  4. 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. ..
  5. Adkins H, Bianco C, Schiffer S, Rayhorn P, Zafari M, Cheung A, et al. Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. J Clin Invest. 2003;112:575-87 pubmed
    ..These data validate that functional blockade of Cripto inhibits tumor growth and highlight antibodies that block Cripto signaling mediated through its CFC domain as an important class of antibodies for further therapeutic development. ..
  6. Ehata S, Hanyu A, Fujime M, Katsuno Y, Fukunaga E, Goto K, et al. Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci. 2007;98:127-33 pubmed
    ..These findings suggest that TbetaR-I kinase inhibitors such as Ki26894 may be useful for blocking the progression of advanced cancers. ..
  7. Strizzi L, Bianco C, Normanno N, Salomon D. Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis. Oncogene. 2005;24:5731-41 pubmed
    ..We also briefly discuss evidence suggesting that Cripto-1 may be involved in stem cell maintenance. ..
  8. Park S, Lee Y, Seki T, Hong K, Fliess N, Jiang Z, et al. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood. 2008;111:633-42 pubmed
    ..These data indicate that neither ALK5 nor TGFBR2 is required for ALK1 signaling pertinent to the pathogenesis of HHT and suggest that HHT might not be a TGF-beta subfamily disease. ..
  9. Dudas M, Kim J, Li W, Nagy A, Larsson J, Karlsson S, et al. Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion. Dev Biol. 2006;296:298-314 pubmed

More Information


  1. Bertolino P, Holmberg R, Reissmann E, Andersson O, Berggren P, Ibanez C. Activin B receptor ALK7 is a negative regulator of pancreatic beta-cell function. Proc Natl Acad Sci U S A. 2008;105:7246-51 pubmed publisher
    ..We propose that ALK7 plays an important role in regulating the functional plasticity of pancreatic islets, negatively affecting beta-cell function by mediating the effects of activin B on Ca(2+) signaling. ..
  2. Andersson O, Korach Andre M, Reissmann E, Ibanez C, Bertolino P. Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity. Proc Natl Acad Sci U S A. 2008;105:7252-6 pubmed publisher
    ..We propose that GDF3 regulates adipose-tissue homeostasis and energy balance under nutrient overload in part by signaling through the ALK7 receptor. ..
  3. Singh K, Rommel K, Mishra A, Karck M, Haverich A, Schmidtke J, et al. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat. 2006;27:770-7 pubmed
    ..In TGFBR2, five mutations and six polymorphisms were identified. Reexamination of patients with a TGFBR1 or TGFBR2 mutation revealed extensive clinical overlap between patients with MFS1, MFS2, and LDS. ..
  4. Suszko M, Woodruff T. Cell-specificity of transforming growth factor-beta response is dictated by receptor bioavailability. J Mol Endocrinol. 2006;36:591-600 pubmed
    ..It is likely that the ligand-restricted mechanisms employed by the gonadotrope are present in other cells, which could explain the distinct control of many cellular processes by members of the TGFbeta superfamily. ..
  5. Bocciardi R, Bordo D, Di Duca M, Di Rocco M, Ravazzolo R. Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements. Eur J Hum Genet. 2009;17:311-8 pubmed publisher
    ..The novel amino-acid substitution is predicted to influence either the conformation/stability of the GS region or the binding affinity with FKBP12, resulting in a less stringent inhibitory control on the ACVR1 kinase activity...
  6. Loeys B, Chen J, Neptune E, Judge D, Podowski M, Holm T, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37:275-81 pubmed
  7. Xu G, Zhong Y, Munir S, Yang B, Tsang B, Peng C. Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. J Clin Endocrinol Metab. 2004;89:5523-34 pubmed
  8. Jörnvall H, Reissmann E, Andersson O, Mehrkash M, Ibanez C. ALK7, a receptor for nodal, is dispensable for embryogenesis and left-right patterning in the mouse. Mol Cell Biol. 2004;24:9383-9 pubmed
  9. Bernard D. Both SMAD2 and SMAD3 mediate activin-stimulated expression of the follicle-stimulating hormone beta subunit in mouse gonadotrope cells. Mol Endocrinol. 2004;18:606-23 pubmed
    ..Collectively, these data suggest that activins use both SMAD2- and SMAD3-dependent mechanisms to stimulate FSHbeta transcription in mouse gonadotrope cells. ..
  10. Parisi S, D Andrea D, Lago C, Adamson E, Persico M, Minchiotti G. Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells. J Cell Biol. 2003;163:303-14 pubmed
    ..Finally, we show that Nodal antagonists inhibit Cripto-regulated cardiomyocyte induction and differentiation in ES cells. All together our findings provide evidence for a novel role of the Nodal/Cripto/Alk4 pathway in this process. ..
  11. Groppe J, Shore E, Kaplan F. Functional modeling of the ACVR1 (R206H) mutation in FOP. Clin Orthop Relat Res. 2007;462:87-92 pubmed
  12. Nakajima M, Haga N, Takikawa K, Manabe N, Nishimura G, Ikegawa S. The ACVR1 617G>A mutation is also recurrent in three Japanese patients with fibrodysplasia ossificans progressiva. J Hum Genet. 2007;52:473-5 pubmed
    ..We identified the 617G>A mutation in all three patients. Our results suggest that the mutation in the ACVR1 gene is common and recurrent in the global population. ..
  13. Mazerbourg S, Klein C, Roh J, Kaivo Oja N, Mottershead D, Korchynskyi O, et al. Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5. Mol Endocrinol. 2004;18:653-65 pubmed
    ..Because ALK5 is a known receptor for TGF-beta, diverse members of the TGF-beta family of ligands appear to interact with a limited number of receptors in a combinatorial manner to activate two downstream Smad pathways. ..
  14. Sadick H, Sadick M, Gotte K, Naim R, Riedel F, Bran G, et al. Hereditary hemorrhagic telangiectasia: an update on clinical manifestations and diagnostic measures. Wien Klin Wochenschr. 2006;118:72-80 pubmed
  15. Hu T, RamachandraRao S, Siva S, Valancius C, Zhu Y, Mahadev K, et al. Reactive oxygen species production via NADPH oxidase mediates TGF-beta-induced cytoskeletal alterations in endothelial cells. Am J Physiol Renal Physiol. 2005;289:F816-25 pubmed
    ..In conclusion, our studies show for the first time that TGF-beta-induced ROS production in human endothelial cells is via Nox4 and that TGF-beta alteration of cytoskeleton in HUVEC is mediated via a Nox4-dependent pathway. ..
  16. Scharpfenecker M, Van Dinther M, Liu Z, van Bezooijen R, Zhao Q, Pukac L, et al. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci. 2007;120:964-72 pubmed
    ..Taken together, these results suggest that BMP-9 is a physiological ALK1 ligand that plays an important role in the regulation of angiogenesis. ..
  17. Lin G, Chang H, Liu C, Huang P, Wang H, Cheng Y. De novo 617G-A nucleotide mutation in the ACVR1 gene in a Taiwanese patient with fibrodysplasia ossificans progressiva. J Hum Genet. 2006;51:1083-6 pubmed
    ..Pedigree analysis suggests that a de novo mutation in the ACVR1 gene is responsible for the disease in this family. This is the first report of the results of a mutation analysis in a sporadic case of FOP in a Taiwanese patient...
  18. Kaartinen V, Dudas M, Nagy A, Sridurongrit S, Lu M, Epstein J. Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells. Development. 2004;131:3481-90 pubmed
    ..Thus, the type I BMP receptor ALK2 plays an essential cell-autonomous role in the development of the cardiac outflow tract and aortic arch derivatives. ..
  19. Tsuchida K, Nakatani M, Yamakawa N, Hashimoto O, Hasegawa Y, Sugino H. Activin isoforms signal through type I receptor serine/threonine kinase ALK7. Mol Cell Endocrinol. 2004;220:59-65 pubmed
    ..Thus, the differential combination of receptor heterodimers mediates variation in activin isoform signaling. ..
  20. Goumans M, Lebrin F, Valdimarsdottir G. Controlling the angiogenic switch: a balance between two distinct TGF-b receptor signaling pathways. Trends Cardiovasc Med. 2003;13:301-7 pubmed
    ..This review describes the role of TGF-beta in angiogenesis and some of the controversial issues concerning TGF-beta signaling through ALK1 and ALK5 in ECs. ..
  21. Pasche B, Kaklamani V, Hou N, Young T, Rademaker A, Peterlongo P, et al. TGFBR1*6A and cancer: a meta-analysis of 12 case-control studies. J Clin Oncol. 2004;22:756-8 pubmed
  22. Kogame M, Matsuo S, Nakatani M, Kurisaki A, Nishitani H, Tsuchida K, et al. ALK7 is a novel marker for adipocyte differentiation. J Med Invest. 2006;53:238-45 pubmed
    ..These results indicated that ALK7 is a novel marker specifically expressed during the late phase of adipocyte differentiation. Furthermore, our results suggest the possible involvement of nodal or activin B in adipocyte differentiation. ..
  23. Furuya H, Ikezoe K, Wang L, Ohyagi Y, Motomura K, Fujii N, et al. A unique case of fibrodysplasia ossificans progressiva with an ACVR1 mutation, G356D, other than the common mutation (R206H). Am J Med Genet A. 2008;146A:459-63 pubmed publisher
    ..5-Mb region spanning ACVR1 and its neighbor genes suggested that 1067G > A is a de novo mutation. These results give a clue to better understanding of FOP as well as of the mild clinical symptoms in the patient. ..
  24. Andersson O, Bertolino P, Ibanez C. Distinct and cooperative roles of mammalian Vg1 homologs GDF1 and GDF3 during early embryonic development. Dev Biol. 2007;311:500-11 pubmed
  25. Harms P, Chang C. Tomoregulin-1 (TMEFF1) inhibits nodal signaling through direct binding to the nodal coreceptor Cripto. Genes Dev. 2003;17:2624-9 pubmed
    ..Our results demonstrate for the first time that nodal signaling can be regulated by a novel mechanism of blocking the Cripto coreceptor. ..
  26. Wang H, Jiang J, Zhu C, Peng C, Tsang B. Role and regulation of nodal/activin receptor-like kinase 7 signaling pathway in the control of ovarian follicular atresia. Mol Endocrinol. 2006;20:2469-82 pubmed
  27. Shore E, Xu M, Feldman G, Fenstermacher D, Cho T, Choi I, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38:525-7 pubmed
    ..Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP...
  28. Ades L, Sullivan K, Biggin A, Haan E, Brett M, Holman K, et al. FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited. Am J Med Genet A. 2006;140:1047-58 pubmed
  29. Bernard D, Lee K, Santos M. Activin B can signal through both ALK4 and ALK7 in gonadotrope cells. Reprod Biol Endocrinol. 2006;4:52 pubmed
    ..The relative roles of endogenous ALK4 and ALK7 receptors in mediating activin B's effects in these cells have yet to be determined. ..
  30. Gray P, Harrison C, Vale W. Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Proc Natl Acad Sci U S A. 2003;100:5193-8 pubmed
    ..Because activin is a potent inhibitor of cell growth in multiple cell types, these results provide a mechanism that may partially explain the oncogenic action of Cripto. ..
  31. Loeys B, Schwarze U, Holm T, Callewaert B, Thomas G, Pannu H, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788-98 pubmed
    ..Genotyping of patients presenting with symptoms like those of vascular Ehlers-Danlos syndrome may be used to guide therapy, including the use and timing of prophylactic vascular surgery. ..
  32. Wu X, Ma J, Han J, Wang N, Chen Y. Distinct regulation of gene expression in human endothelial cells by TGF-beta and its receptors. Microvasc Res. 2006;71:12-9 pubmed
    ..Our results suggest that ALK1 appears to have important functions in regulating proliferation of ECs, whereas ALK5 tends to modulate cell-cell interaction and cell adhesion and extracellular matrix remodeling. ..
  33. Dudas M, Sridurongrit S, Nagy A, Okazaki K, Kaartinen V. Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest cells. Mech Dev. 2004;121:173-82 pubmed
    ..Based on the present results we conclude that signaling via Alk2 receptors is non-redundant and regulates normal development of a restricted set of structures derived from the cranial neural crest. ..
  34. Jung B, Beck S, Cabral J, Chau E, Cabrera B, Fiorino A, et al. Activin type 2 receptor restoration in MSI-H colon cancer suppresses growth and enhances migration with activin. Gastroenterology. 2007;132:633-44 pubmed
    ..Activin is growth suppressive and enhances migration similar to transforming growth factor beta in colon cancer, indicating that abrogation of the effects of activin contribute to the pathogenesis of MSI-H colon cancers. ..
  35. 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. ..
  36. Cheng S, Olale F, Bennett J, Brivanlou A, Schier A. EGF-CFC proteins are essential coreceptors for the TGF-beta signals Vg1 and GDF1. Genes Dev. 2003;17:31-6 pubmed
    ..These results establish that multiple TGF-beta signals converge on Activin receptor/EGF-CFC complexes and suggest a more widespread requirement for coreceptors in TGF-beta signaling than anticipated previously. ..
  37. Bondestam J, Huotari M, Moren A, Ustinov J, Kaivo Oja N, Kallio J, et al. cDNA cloning, expression studies and chromosome mapping of human type I serine/threonine kinase receptor ALK7 (ACVR1C). Cytogenet Cell Genet. 2001;95:157-62 pubmed
    ..Infection with Ad-caALK7 of MIN6 insulinoma cells, in which ALK7 has previously been shown to be endogenously expressed, led to a marked increase in the phosphorylation of Smad2, a signaling molecule also used by TGF-betas and activins. ..
  38. Bianco C, Adkins H, Wechselberger C, Seno M, Normanno N, De Luca A, et al. Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells. Mol Cell Biol. 2002;22:2586-97 pubmed
    ..In contrast, CR-1 stimulation of mitogen-activated protein kinase and AKT in these cells is independent of Nodal and ALK4, suggesting that CR-1 may modulate different signaling pathways to mediate its different functional roles. ..
  39. Sakuma R, Ohnishi Yi Y, Meno C, Fujii H, Juan H, Takeuchi J, et al. Inhibition of Nodal signalling by Lefty mediated through interaction with common receptors and efficient diffusion. Genes Cells. 2002;7:401-12 pubmed
    ..Efficient inhibition of Nodal signals by Lefty may involve competitive binding of Lefty to the common receptors and faster diffusion of Lefty. ..
  40. Liu X, Nagarajan R, Vale W, Chen Y. Phosphorylation regulation of the interaction between Smad7 and activin type I receptor. FEBS Lett. 2002;519:93-8 pubmed
    ..These studies not only illustrated the counter regulatory function of Smad7 on activin signaling, but also indicated the involvement of phosphorylation at activin type I receptor in the inhibitory action of Smad7. ..
  41. Yan Y, Liu J, Luo Y, E C, Haltiwanger R, Abate Shen C, et al. Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. Mol Cell Biol. 2002;22:4439-49 pubmed
    ..Our findings highlight the significance of extracellular modulation of ligand activity as an important means of regulating TGF beta signaling pathways during vertebrate development. ..
  42. Bianco C, Strizzi L, Rehman A, Normanno N, Wechselberger C, Sun Y, et al. A Nodal- and ALK4-independent signaling pathway activated by Cripto-1 through Glypican-1 and c-Src. Cancer Res. 2003;63:1192-7 pubmed
    ..Finally, an active Src kinase is necessary for CR-1 to induce in vitro transformation and migration in mouse mammary epithelial cells. ..
  43. Lamouille S, Mallet C, Feige J, Bailly S. Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis. Blood. 2002;100:4495-501 pubmed
    ..Taken together, our results suggest that ALK-1 is implicated in the maturation phase of angiogenesis. Disruption of this latter phase of angiogenesis may be an important step in the development of hereditary hemorrhagic telangiectasia. ..
  44. Bennett D, Alphey L. PP1 binds Sara and negatively regulates Dpp signaling in Drosophila melanogaster. Nat Genet. 2002;31:419-23 pubmed
    ..Together these data suggest that PP1c is targeted to Dpp receptor complexes by Sara, where it acts as a negative regulator of Dpp signaling by affecting the phosphorylation state of the type I receptor. ..
  45. Inman G, Nicolás F, Callahan J, Harling J, Gaster L, Reith A, et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 2002;62:65-74 pubmed
    ..SB-431542 has no effect on components of the ERK, JNK, or p38 MAP kinase pathways or on components of the signaling pathways activated in response to serum. ..
  46. Laping N, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, et al. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol. 2002;62:58-64 pubmed
    ..e., FN), whereas others seem to be activated via ALK5 signaling independent of the p38 MAPK pathway (i.e., col Ialpha1). ..
  47. Shore E, Kaplan F. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol. 2010;6:518-27 pubmed publisher
  48. Castañares C, Redondo Horcajo M, Magán Marchal N, Lamas S, Rodriguez Pascual F. Transforming growth factor-beta receptor requirements for the induction of the endothelin-1 gene. Exp Biol Med (Maywood). 2006;231:700-3 pubmed
  49. Yamasaki K, Toriu N, Hanakawa Y, Shirakata Y, Sayama K, Takayanagi A, et al. Keratinocyte growth inhibition by high-dose epidermal growth factor is mediated by transforming growth factor beta autoinduction: a negative feedback mechanism for keratinocyte growth. J Invest Dermatol. 2003;120:1030-7 pubmed
    ..These data demonstrate that an autocrine transforming growth factor beta1-ALK5 pathway is a negative feedback mechanism for epidermal growth factor-induced normal human keratinocyte growth. ..
  50. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, et al. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med. 2003;9:964-8 pubmed
    ..Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease. ..
  51. Yndestad A, Ueland T, Øie E, Florholmen G, Halvorsen B, Attramadal H, et al. Elevated levels of activin A in heart failure: potential role in myocardial remodeling. Circulation. 2004;109:1379-85 pubmed
  52. El Shabrawi Caelen L, Kerl K, Cerroni L, Soyer H, Kerl H. Cutaneous inflammatory pseudotumor--a spectrum of various diseases?. J Cutan Pathol. 2004;31:605-11 pubmed
    ..Cutaneous PCG is a discrete disorder biologically distinct from conventional IMT representing a reaction pattern that is also found in disorders, such as spirochete-induced fibroid nodules and localized chronic fibrosing vasculitis. ..
  53. Qiu W, Schönleben F, Li X, Su G. Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4. Cancer Lett. 2007;245:163-70 pubmed