ACVR1B explained

Activin receptor type-1B is a protein that in humans is encoded by the ACVR1B gene.^{[1] [2]}

ACVR1B or ALK-4 acts as a transducer of activin or activin-like ligands (e.g., inhibin) signals. Activin binds to either ACVR2A or ACVR2B and then forms a complex with ACVR1B. These go on to recruit the R-SMADs SMAD2 or SMAD3.^[3] ACVR1B also transduces signals of nodal, GDF-1, and Vg1; however, unlike activin, they require other coreceptor molecules such as the protein Cripto.^[4]

Function

Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I (I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling, and type II receptors are required for binding ligands and expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type IB receptor, composed of 11 exons. Alternative splicing and alternative polyadenylation result in 3 fully described transcript variants. The mRNA expression of variants 1, 2, and 3 is confirmed, and a potential fourth variant contains an alternative exon 8 and lacks exons 9 through 11, but its mRNA expression has not been confirmed.^[2]

Interactions

ACVR1B has been shown to interact with

• ACVR2A,^[5] and ACVR2B^{[6] [7]}

Further reading

• Welt CK . The physiology and pathophysiology of inhibin, activin and follistatin in female reproduction . Curr. Opin. Obstet. Gynecol. . 14 . 3 . 317–23 . 2002 . 12032389 . 10.1097/00001703-200206000-00012 . 44327401 .
• 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 . Mol. Cell. Biol. . 15 . 7 . 3479–86 . 1995 . 7791754 . 230584 . 10.1128/mcb.15.7.3479.
• Xu J, Matsuzaki K, McKeehan K, Wang F, Kan M, McKeehan WL . Genomic structure and cloned cDNAs predict that four variants in the kinase domain of serine/threonine kinase receptors arise by alternative splicing and poly(A) addition . Proc. Natl. Acad. Sci. U.S.A. . 91 . 17 . 7957–61 . 1994 . 8058741 . 44523 . 10.1073/pnas.91.17.7957 . 1994PNAS...91.7957X . free .
• Cárcamo J, Weis FM, Ventura F, Wieser R, Wrana JL, Attisano L, Massagué J . Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin . Mol. Cell. Biol. . 14 . 6 . 3810–21 . 1994 . 8196624 . 358748 . 10.1128/MCB.14.6.3810.
• De Winter JP, De Vries CJ, Van Achterberg TA, Ameerun RF, Feijen A, Sugino H, De Waele P, Huylebroeck D, Verschueren K, Van Den Eijden-Van Raaij AJ . Truncated activin type II receptors inhibit bioactivity by the formation of heteromeric complexes with activin type I. receptors . Exp. Cell Res. . 224 . 2 . 323–34 . 1996 . 8612709 . 10.1006/excr.1996.0142 .
• Attisano L, Wrana JL, Montalvo E, Massagué J . Activation of signalling by the activin receptor complex . Mol. Cell. Biol. . 16 . 3 . 1066–73 . 1996 . 8622651 . 231089 . 10.1128/MCB.16.3.1066.
• Lebrun JJ, Vale WW . Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation . Mol. Cell. Biol. . 17 . 3 . 1682–91 . 1997 . 9032295 . 231893 . 10.1128/MCB.17.3.1682.
• Röijer E, Miyazono K, Aström AK, Geurts van Kessel A, ten Dijke P, Stenman G . Chromosomal localization of three human genes encoding members of the TGF-beta superfamily of type I serine/threonine kinase receptors . Mamm. Genome . 9 . 3 . 266–8 . 1998 . 9501322 . 10.1007/s003359900745 . 21839781 .
• Souchelnytskyi S, Nakayama T, Nakao A, Morén A, Heldin CH, Christian JL, ten Dijke P . Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and transforming growth factor-beta receptors . J. Biol. Chem. . 273 . 39 . 25364–70 . 1998 . 9738003 . 10.1074/jbc.273.39.25364 . free .
• Hashimoto O, Yamato K, Koseki T, Ohguchi M, Ishisaki A, Shoji H, Nakamura T, Hayashi Y, Sugino H, Nishihara T . The role of activin type I receptors in activin A-induced growth arrest and apoptosis in mouse B-cell hybridoma cells . Cell. Signal. . 10 . 10 . 743–9 . 1998 . 9884026 . 10.1016/S0898-6568(98)00021-7 .
• Lebrun JJ, Takabe K, Chen Y, Vale W . Roles of pathway-specific and inhibitory Smads in activin receptor signaling . Mol. Endocrinol. . 13 . 1 . 15–23 . 1999 . 9892009 . 10.1210/mend.13.1.0218 . 26825706 . free .
• Gray PC, Greenwald J, Blount AL, Kunitake KS, Donaldson CJ, Choe S, Vale W . Identification of a binding site on the type II activin receptor for activin and inhibin . J. Biol. Chem. . 275 . 5 . 3206–12 . 2000 . 10652306 . 10.1074/jbc.275.5.3206 . free .
• Zhou Y, Sun H, Danila DC, Johnson SR, Sigai DP, Zhang X, Klibanski A . Truncated activin type I receptor Alk4 isoforms are dominant negative receptors inhibiting activin signaling . Mol. Endocrinol. . 14 . 12 . 2066–75 . 2000 . 11117535 . 10.1210/mend.14.12.0570 . free .
• Su GH, Bansal R, Murphy KM, Montgomery E, Yeo CJ, Hruban RH, Kern SE . ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma . Proc. Natl. Acad. Sci. U.S.A. . 98 . 6 . 3254–7 . 2001 . 11248065 . 30640 . 10.1073/pnas.051484398 . 2001PNAS...98.3254S . free .
• Chapman SC, Woodruff TK . Modulation of activin signal transduction by inhibin B and inhibin-binding protein (INhBP) . Mol. Endocrinol. . 15 . 4 . 668–79 . 2001 . 11266516 . 10.1210/mend.15.4.0616 . free .
• Wurthner JU, Frank DB, Felici A, Green HM, Cao Z, Schneider MD, McNally JG, Lechleider RJ, Roberts AB . Transforming growth factor-beta receptor-associated protein 1 is a Smad4 chaperone . J. Biol. Chem. . 276 . 22 . 19495–502 . 2001 . 11278302 . 10.1074/jbc.M006473200 . free .
• Parks WT, Frank DB, Huff C, Renfrew Haft C, Martin J, Meng X, de Caestecker MP, McNally JG, Reddi A, Taylor SI, Roberts AB, Wang T, Lechleider RJ . Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases . J. Biol. Chem. . 276 . 22 . 19332–9 . 2001 . 11279102 . 10.1074/jbc.M100606200 . free .
• Birkey Reffey S, Wurthner JU, Parks WT, Roberts AB, Duckett CS . X-linked inhibitor of apoptosis protein functions as a cofactor in transforming growth factor-beta signaling . J. Biol. Chem. . 276 . 28 . 26542–9 . 2001 . 11356828 . 10.1074/jbc.M100331200 . free .
• Bianco C, Adkins HB, Wechselberger C, Seno M, Normanno N, De Luca A, Sun Y, Khan N, Kenney N, Ebert A, Williams KP, Sanicola M, Salomon DS . Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells . Mol. Cell. Biol. . 22 . 8 . 2586–97 . 2002 . 11909953 . 133714 . 10.1128/MCB.22.8.2586-2597.2002 .

Notes and References

1. ten Dijke P, Ichijo H, Franzén P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K . Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity . Oncogene . 8 . 10 . 2879–87 . October 1993 . 8397373 .
2. Web site: Entrez Gene: ACVR1B activin A receptor, type IB.
3. Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS . 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. . 62 . 1 . 65–74 . 2002 . 12065756 . 10.1124/mol.62.1.65 . 15185199 .
4. Harrison CA, Gray PC, Koerber SC, Fischer W, Vale W . Identification of a functional binding site for activin on the type I receptor ALK4 . J. Biol. Chem. . 278 . 23 . 21129–35 . 2003 . 12665502 . 10.1074/jbc.M302015200 . free .
5. Lebrun JJ, Takabe K, Chen Y, Vale W . Roles of pathway-specific and inhibitory Smads in activin receptor signaling . Mol. Endocrinol. . 13 . 1 . 15–23 . January 1999 . 9892009 . 10.1210/mend.13.1.0218 . 26825706 . free .
6. Attisano L, Wrana JL, Montalvo E, Massagué J . Activation of signalling by the activin receptor complex . Mol. Cell. Biol. . 16 . 3 . 1066–73 . March 1996 . 8622651 . 231089 . 10.1128/MCB.16.3.1066.
7. De Winter JP, De Vries CJ, Van Achterberg TA, Ameerun RF, Feijen A, Sugino H, De Waele P, Huylebroeck D, Verschueren K, Van Den Eijden-Van Raaij AJ . Truncated activin type II receptors inhibit bioactivity by the formation of heteromeric complexes with activin type I. receptors . Exp. Cell Res. . 224 . 2 . 323–34 . May 1996 . 8612709 . 10.1006/excr.1996.0142 .