Genomes and Genes
type ii activin receptors
Summary: One of the two types of ACTIVIN RECEPTORS. They are membrane protein kinases belonging to the family of PROTEIN-SERINE-THREONINE KINASES. The major type II activin receptors are ActR-IIA and ActR-IIB.
- Jung B, Smith E, Doctolero R, Gervaz P, Alonso J, Miyai K, et al. Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers. Int J Cancer. 2006;118:2509-13 pubmed
- Kuehl H, Caselitz M, Hasenkamp S, Wagner S, El Harith E, Manns M, et al. Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations. Hum Mutat. 2005;25:320 pubmed..In this study, we have identified five novel ALK1 and one ENG disease-causing mutations. We conclude that hepatic manifestation in HHT patients is associated with mutations in the ALK1 gene, but rarely with ENG mutations. ..
- 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. ..
- Xia Y, Yu P, Sidis Y, Beppu H, Bloch K, Schneyer A, et al. Repulsive guidance molecule RGMa alters utilization of bone morphogenetic protein (BMP) type II receptors by BMP2 and BMP4. J Biol Chem. 2007;282:18129-40 pubmed..These findings suggest that RGMa facilitates the use of ActRIIA by endogenous BMP2 and BMP4 ligands that otherwise prefer signaling via BMPRII and that increased utilization of ActRIIA leads to generation of an enhanced BMP signal. ..
- Bossler A, Richards J, George C, Godmilow L, Ganguly A. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006;27:667-75 pubmed..As many of the complications of HHT disease can be prevented, a confirmed molecular diagnosis provides an opportunity for early detection of AVMs and management of the disease. ..
- Song J, Oh S, Schrewe H, Nomura M, Lei H, Okano M, et al. The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev Biol. 1999;213:157-69 pubmedThe type II activin receptors, ActRIIA and ActRIIB, have been shown to play critical roles in axial patterning and organ development in mice...
- Letteboer T, Zewald R, Kamping E, de Haas G, Mager J, Snijder R, et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005;116:8-16 pubmed..In 7% of the families no ENG or ALK1 mutation was found. The mutations detected were deletions, insertions, nonsense, missense and splice site mutations. The majority were novel mutations. ..
- Lee S, Reed L, Davies M, Girgenrath S, Goad M, Tomkinson K, et al. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci U S A. 2005;102:18117-22 pubmed..Finally, we provide genetic evidence that these ligands signal through both activin type II receptors, ACVR2 and ACVR2B, to regulate muscle growth in vivo. ..
- Finnson K, Parker W, Ten Dijke P, Thorikay M, Philip A. ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. J Bone Miner Res. 2008;23:896-906 pubmed publisher..Our results suggest that ALK1 and ALK5 display opposing functions in human chondrocytes, implicating an essential role for ALK1 in the regulation of TGF-beta signaling and function in these cells. ..
- 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. ..
- Li L, Zhao X, Wang B. Down-regulation of transforming growth factor beta 1/activin receptor-like kinase 1 pathway gene expression by herbal compound 861 is related to deactivation of LX-2 cells. World J Gastroenterol. 2008;14:2894-9 pubmed..Cpd861 can restrain the activation of LX-2 cells by inhibiting the TGF beta 1/ALK1/Smad1 pathway. ..
- 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. ..
- Mori Y, Yin J, Rashid A, Leggett B, Young J, Simms L, et al. Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability. Cancer Res. 2001;61:6046-9 pubmed..8%), and EBP1/PA2G4 (20.9%). This genome-wide approach identifies coding region MSI in genes or pathways not implicated previously in colorectal tumorigenesis, which may merit functional study or other additional analysis. ..
- Harrison R, Flanagan J, Sankelo M, Abdalla S, Rowell J, Machado R, et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003;40:865-71 pubmed..Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease. ..
- Lesca G, Plauchu H, Coulet F, Lefebvre S, Plessis G, Odent S, et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004;23:289-99 pubmed..1231C>T (p.Arg411Trp), c.1232G>C (p.Arg411Pro), and c.1232G>A (p.Arg411Gln) were found in seven, two, and one patients, respectively. Haplotype analysis was in favor of both a founder effect and a mutation hot-spot. ..
- Seki T, Hong K, Yun J, Kim S, Oh S. Isolation of a regulatory region of activin receptor-like kinase 1 gene sufficient for arterial endothelium-specific expression. Circ Res. 2004;94:e72-7 pubmed..The full text of this article is available online at http://circres.ahajournals.org. ..
- Bayrak Toydemir P, McDonald J, Markewitz B, Lewin S, Miller F, Chou L, et al. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A. 2006;140:463-70 pubmed..We conclude that HHT2 has a later onset than HHT1 and the former may disproportionately involve smaller vessels in tissues with more significant vascular remodeling. ..
- Thompson T, Woodruff T, Jardetzky T. Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions. EMBO J. 2003;22:1555-66 pubmed
- Olivieri C, Mira E, Delù G, Pagella F, Zambelli A, Malvezzi L, et al. Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia. J Med Genet. 2002;39:E39 pubmed
- David L, Mallet C, Keramidas M, Lamandé N, Gasc J, Dupuis Girod S, et al. Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ Res. 2008;102:914-22 pubmed publisher..Taken together, our results demonstrate that BMP9, circulating under a biologically active form, is a potent antiangiogenic factor that is likely to play a physiological role in the control of adult blood vessel quiescence. ..
- Scherner O, Meurer S, Tihaa L, Gressner A, Weiskirchen R. Endoglin differentially modulates antagonistic transforming growth factor-beta1 and BMP-7 signaling. J Biol Chem. 2007;282:13934-43 pubmed..Finally, we found that the transient overexpression of endoglin, previously shown to inhibit TGF-beta1-induced ALK-5/Smad3 signaling, enhanced the BMP-7/Smad1/Smad5 pathway. ..
- Lesca G, Burnichon N, Raux G, Tosi M, Pinson S, Marion M, et al. Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat. 2006;27:598 pubmed..Our results also emphasize the higher prevalence of large insertions/deletions in ENG and the predominance of ACVRL1 over ENG mutations. ..
- Gamer L, Nove J, Levin M, Rosen V. BMP-3 is a novel inhibitor of both activin and BMP-4 signaling in Xenopus embryos. Dev Biol. 2005;285:156-68 pubmed..Our results identify BMP-3 as a novel antagonist of both activin and BMPs and uncover how some of the diverse developmental processes that are regulated by both activin and BMP signaling can be modulated during embryogenesis. ..
- Harrison R, Berger R, Haworth S, Tulloh R, Mache C, Morrell N, et al. Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood. Circulation. 2005;111:435-41 pubmed..The cause of PAH presenting in childhood is heterogeneous in nature, with genetic defects of transforming growth factor-beta receptors playing a critical role. ..
- Greenwald J, Groppe J, Gray P, Wiater E, Kwiatkowski W, Vale W, et al. The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol Cell. 2003;11:605-17 pubmed..Taken together, our results provide a view of the ligand-mediated cooperative assembly of BMP and activin receptors that does not rely on receptor-receptor contacts. ..
- Hempen P, Zhang L, Bansal R, Iacobuzio Donahue C, Murphy K, Maitra A, et al. Evidence of selection for clones having genetic inactivation of the activin A type II receptor (ACVR2) gene in gastrointestinal cancers. Cancer Res. 2003;63:994-9 pubmed..This evidence is compatible with a high degree of selection for inactivation of the ACVR2 gene in tumorigenesis, supporting ACVR2 as a candidate tumor suppressor gene in gastrointestinal cancers. ..
- 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. ..
- Chung H, Young D, Lopez C, Le T, Lee J, Ream Robinson D, et al. Mutation rates of TGFBR2 and ACVR2 coding microsatellites in human cells with defective DNA mismatch repair. PLoS ONE. 2008;3:e3463 pubmed publisher..The -1 bp frameshift mutation rates of TGFBR2 and ACVR2 microsatellite sequences are dependent upon the human MMR background. ..
- Kosaki R, Gebbia M, Kosaki K, Lewin M, Bowers P, Towbin J, et al. Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am J Med Genet. 1999;82:70-6 pubmed..Neither of these nucleotide changes has been found in 200 control chromosomes. We conclude that ACVR2B mutations are present only rarely among human LR axis malformation cases. ..
- 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. ..
- Morrison B, Lachey J, Warsing L, Ting B, Pullen A, Underwood K, et al. A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2009;217:258-68 pubmed publisher..The improved function of SOD1(G93A) transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-beta pathway inhibitors to increase muscle strength in patients with ALS. ..
- Nagaso H, Suzuki A, Tada M, Ueno N. Dual specificity of activin type II receptor ActRIIb in dorso-ventral patterning during zebrafish embryogenesis. Dev Growth Differ. 1999;41:119-33 pubmed..These results suggest that ActRIIb at least has dual roles in both activin and BMP signaling pathways during zebrafish embryogenesis. ..
- Allendorph G, Vale W, Choe S. Structure of the ternary signaling complex of a TGF-beta superfamily member. Proc Natl Acad Sci U S A. 2006;103:7643-8 pubmed
- 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. ..
- Lux A, Salway F, Dressman H, Kröner Lux G, Hafner M, Day P, et al. ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-beta and constitutively active receptor induced gene expression. BMC Cardiovasc Disord. 2006;6:13 pubmed..The angiogenesis related genes might be potential HHT modifier genes. In addition, the results suggest endothelial cell type specific ALK1 and TGF-beta signalling. ..
- Schulte C, Geisthoff U, Lux A, Kupka S, Zenner H, Blin N, et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005;25:595 pubmed..Our results demonstrate the importance of ACVRL1 and ENG mutations in German HHT patients displaying mutation frequencies over 80%. ..
- van den Driesche S, Mummery C, Westermann C. Hereditary hemorrhagic telangiectasia: an update on transforming growth factor beta signaling in vasculogenesis and angiogenesis. Cardiovasc Res. 2003;58:20-31 pubmed..Here, we review the current status of reported mutations in the context of the clinical manifestations and the effects on the vessel wall both in patients and in animal models of the disease. ..
- Abdalla S, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet. 2006;43:97-110 pubmed..Current knowledge on the genetics of HHT is summarised, including the pathways that link the genes responsible for HHT and the potential mechanisms underlying the pathogenesis of the disease. ..
- Abdalla S, Cymerman U, Rushlow D, Chen N, Stoeber G, Lemire E, et al. Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia. Hum Mutat. 2005;25:320-1 pubmed..P378H). The proband and his two daughters, who also carried the familial mutation, all suffered from gastrointestinal (GI) bleeding. In addition, we report seven newly identified polymorphisms and summarize all known ones in both genes. ..
- Abdalla S, Geisthoff U, Bonneau D, Plauchu H, McDonald J, Kennedy S, et al. Visceral manifestations in hereditary haemorrhagic telangiectasia type 2. J Med Genet. 2003;40:494-502 pubmed..These findings, however, stress the need for an early diagnosis of HHT that can be useful for the early control of associated visceral involvement. ..
- Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jais X, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010;181:851-61 pubmed publisher..Despite less severe initial hemodynamics and similar management, these patients had worse prognosis compared with other patients with PAH, suggesting more rapid disease progression. ..
- Ota T, Fujii M, Sugizaki T, Ishii M, Miyazawa K, Aburatani H, et al. Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells. J Cell Physiol. 2002;193:299-318 pubmed..These results revealed some new targets of TGF-beta in endothelial cells, and differences in transcriptional regulation patterns between ALK-1 and ALK-5. ..
- Marchuk D, Srinivasan S, Squire T, Zawistowski J. Vascular morphogenesis: tales of two syndromes. Hum Mol Genet. 2003;12 Spec No 1:R97-112 pubmed..Emerging but intriguing tales are being told by the genes (and their protein products) mutated in these disorders. ..
- Abdalla S, Cymerman U, Johnson R, Deber C, Letarte M. Disease-associated mutations in conserved residues of ALK-1 kinase domain. Eur J Hum Genet. 2003;11:279-87 pubmed
- Sabba C, Pasculli G, Lenato G, Suppressa P, Lastella P, Memeo M, et al. Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost. 2007;5:1149-57 pubmed..The ENG gene should be first targeted for mutational screening in the presence of large PAVM in patients < 45 years. ..
- Harrington A, Morris Triggs S, Ruotolo B, Robinson C, Ohnuma S, Hyvonen M. Structural basis for the inhibition of activin signalling by follistatin. EMBO J. 2006;25:1035-45 pubmed..The structure provides a detailed description of the inhibitory mechanism and gives insights into interactions of follistatin with other TGF-beta family proteins. ..
- Gallione C, Richards J, Letteboer T, Rushlow D, Prigoda N, Leedom T, et al. SMAD4 mutations found in unselected HHT patients. J Med Genet. 2006;43:793-7 pubmed..HHT patients with SMAD4 mutations should be screened for colonic and gastric polyps associated with JP. ..
- Lee Y, Hong K, Yun J, Oh S. Generation of activin receptor type IIB isoform-specific hypomorphic alleles. Genesis. 2006;44:487-94 pubmed..In this study, we demonstrate that this phenomenon is most likely due to the reduction in the expressed Acvr2b(4) levels rather than to the functional deficiency of the Acvr2b(4) isoform itself. ..
- Bayrak Toydemir P, McDonald J, Akarsu N, Toydemir R, Calderon F, Tuncali T, et al. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet A. 2006;140:2155-62 pubmed..Further studies of the candidate region and the identification of the gene responsible for the vascular anomalies in this family will add to our understanding of vascular morphogenesis and related disorders. ..
- Lee S, McPherron A. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci U S A. 2001;98:9306-11 pubmed..Our findings suggest that the propeptide, follistatin, or other molecules that block signaling through this pathway may be useful agents for enhancing muscle growth for both human therapeutic and agricultural applications. ..