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ACVR1B  -  activin A receptor, type IB

Homo sapiens

Synonyms: ACTR-IB, ACTRIB, ACVRLK4, ALK-4, ALK4, ...
 
 
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Disease relevance of ACVR1B

  • Here we describe the gene structure and novel somatic mutations of the activin type I receptor, ACVR1B, in pancreatic cancer [1].
  • Activin type I receptors, SKR1 and SKR2, were first cloned from well differentiated human hepatoma cells (HepG2) [2].
  • Human pituitary tumors specifically express alternatively spliced activin type I receptor Alk4 mRNAs, producing C-terminus truncated isoforms designated Alk4-2, 4-3, and 4-4 [3].
  • Isoform analysis of the major functional type I activin receptor alk4 revealed the full-length transcript SKR2-1 and transcripts for the partially truncated proteins SKR2-2 and SKR2-3 in normal thyroids and goiters [4].
 

High impact information on ACVR1B

 

Biological context of ACVR1B

 

Anatomical context of ACVR1B

  • Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells [11].
  • These results indicate that GDF-1 and Nodal converge on ALK4 in the anterior primitive streak to control the formation of organizing centers that are necessary for normal forebrain and branchial arch development [12].
  • Dpr2 is localized in late endosomes, binds to the TGFbeta receptors ALK5 and ALK4, and accelerates lysosomal degradation of these receptors [13].
  • When each of these truncated Alk4 receptors was stably transfected into K562 cells, activin-induced expression of an endogenous gene, junB, was blocked, indicating that inhibition of gene expression also occurred at the chromosomal level [14].
 

Associations of ACVR1B with chemical compounds

  • Activins, like other members of the transforming growth factor-beta (TGF-beta) superfamily, initiate signaling by assembling a complex of two types of transmembrane serine/threonine receptor kinases classified as type II (ActRII or ActRIIB) and type I (ALK4) [9].
  • We have identified five hydrophobic amino acid residues on the ALK4 extracellular domain (Leu40, Ile70, Val73, Leu75, and Pro77) that, when mutated to alanine, have substantial effects on ALK4-trunc dominant negative activity [9].
 

Physical interactions of ACVR1B

  • In addition, eleven mutants partially affected activin binding to ALK4 [9].
 

Regulatory relationships of ACVR1B

  • Activin stimulates the association of InhBP and Alk4, and inhibin B, but not inhibin A, interferes with InhBP-Alk4 complex formation [15].
 

Other interactions of ACVR1B

  • SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7 [16].
  • ALK1, ALK3, and ALK4 mRNAs were found in both normal and neoplastic pituitary cells [8].
  • Our results indicate that there is only a partial overlap of the binding sites on ALK4 and ALK3 for activin-A and bone morphogenetic protein-2, respectively [9].
  • In addition, when cells are maintained undifferentiated by treatment with the GSK3-inhibitor, BIO, high expression of nodal, lefty-A, and lefty-B also requires activation of ALK4/5/7 [17].
  • Activins control many physiologic and pathophysiologic processes in multiple tissues and, like other TGF-beta superfamily members, signal via type II (ActRII/IIB) and type I (ALK4) receptor serine kinases [18].
 

Analytical, diagnostic and therapeutic context of ACVR1B

References

  1. ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma. Su, G.H., Bansal, R., Murphy, K.M., Montgomery, E., Yeo, C.J., Hruban, R.H., Kern, S.E. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  2. Inhibin antagonizes inhibition of liver cell growth by activin by a dominant-negative mechanism. Xu, J., McKeehan, K., Matsuzaki, K., McKeehan, W.L. J. Biol. Chem. (1995) [Pubmed]
  3. Overexpression of wild-type activin receptor alk4-1 restores activin antiproliferative effects in human pituitary tumor cells. Danila, D.C., Zhang, X., Zhou, Y., Haidar, J.N., Klibanski, A. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  4. Activin A and activin receptors in the human thyroid: a link to the female predominance of goiter? Schulte, K.M., Jonas, C., Krebs, R., Röher, H.D. Horm. Metab. Res. (2000) [Pubmed]
  5. Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Lewis, K.A., Gray, P.C., Blount, A.L., MacConell, L.A., Wiater, E., Bilezikjian, L.M., Vale, W. Nature (2000) [Pubmed]
  6. Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Gray, P.C., Harrison, C.A., Vale, W. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Murphy, K.M., Brune, K.A., Griffin, C., Sollenberger, J.E., Petersen, G.M., Bansal, R., Hruban, R.H., Kern, S.E. Cancer Res. (2002) [Pubmed]
  8. Tumor-specific expression and alternate splicing of messenger ribonucleic acid encoding activin/transforming growth factor-beta receptors in human pituitary adenomas. Alexander, J.M., Bikkal, H.A., Zervas, N.T., Laws, E.R., Klibanski, A. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  9. Identification of a functional binding site for activin on the type I receptor ALK4. Harrison, C.A., Gray, P.C., Koerber, S.C., Fischer, W., Vale, W. J. Biol. Chem. (2003) [Pubmed]
  10. Phosphorylation regulation of the interaction between Smad7 and activin type I receptor. Liu, X., Nagarajan, R.P., Vale, W., Chen, Y. FEBS Lett. (2002) [Pubmed]
  11. Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells. Bianco, C., Adkins, H.B., Wechselberger, C., Seno, M., Normanno, N., De Luca, A., Sun, Y., Khan, N., Kenney, N., Ebert, A., Williams, K.P., Sanicola, M., Salomon, D.S. Mol. Cell. Biol. (2002) [Pubmed]
  12. Synergistic interaction between Gdf1 and Nodal during anterior axis development. Andersson, O., Reissmann, E., Jörnvall, H., Ibáñez, C.F. Dev. Biol. (2006) [Pubmed]
  13. Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Zhang, L., Zhou, H., Su, Y., Sun, Z., Zhang, H., Zhang, L., Zhang, Y., Ning, Y., Chen, Y.G., Meng, A. Science (2004) [Pubmed]
  14. Truncated activin type I receptor Alk4 isoforms are dominant negative receptors inhibiting activin signaling. Zhou, Y., Sun, H., Danila, D.C., Johnson, S.R., Sigai, D.P., Zhang, X., Klibanski, A. Mol. Endocrinol. (2000) [Pubmed]
  15. Modulation of activin signal transduction by inhibin B and inhibin-binding protein (INhBP). Chapman, S.C., Woodruff, T.K. Mol. Endocrinol. (2001) [Pubmed]
  16. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. DaCosta Byfield, S., Major, C., Laping, N.J., Roberts, A.B. Mol. Pharmacol. (2004) [Pubmed]
  17. Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3. Besser, D. J. Biol. Chem. (2004) [Pubmed]
  18. An activin mutant with disrupted ALK4 binding blocks signaling via type II receptors. Harrison, C.A., Gray, P.C., Fischer, W.H., Donaldson, C., Choe, S., Vale, W. J. Biol. Chem. (2004) [Pubmed]
  19. Activin receptors: cellular signalling by receptor serine kinases. Zimmerman, C.M., Mathews, L.S. Biochem. Soc. Symp. (1996) [Pubmed]
 
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