ACVRL1 explained

Serine/threonine-protein kinase receptor R3 is an enzyme that in humans is encoded by the ACVRL1 gene.^{[1] [2]}

ACVRL1 is a receptor in the TGF beta signaling pathway. It is also known as activin receptor-like kinase 1, or ALK1.

Function

This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hereditary hemorrhagic telangiectasia (HHT) type 2, also known as Rendu-Osler-Weber syndrome 2.^[3]

Pathology

Germline mutations of ACVRL1 are associated with:

• hereditary hemorrhagic telangiectasia type 2 (Rendu-Osler-Weber syndrome 2)^[4]
• Pulmonary arteriovenous malformations^[5]

Somatic mosaicism in ACVRL1 are associated with severe pulmonary arterial hypertension.^[6]

ACVRL1 directly interacts with low-density lipoprotein (LDL), which implies that it might initiate the early phases of atherosclerosis.^[7]

Abnormal activity of ACVRL1 has been found to be closely associated with idiopathic pulmonary arterial hypertension.

As a drug target

• Dalantercept is an experimental ALK1 inhibitor.^[8]

Closely/family related kinases

(Not to be confused with anaplastic lymphoma kinase (ALK))
ALK4 is ACVR1B, ALK7 is ACVR1C, and ALK5 is [part of] the TGF-β type I receptor.^[9]

See also

• TGF beta signaling pathway, see summary table for ALK*

Further reading

• Attisano L, Cárcamo J, Ventura F, Weis FM, Massagué J, Wrana JL . Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors . Cell . 75 . 4 . 671–80 . November 1993 . 8242742 . 10.1016/0092-8674(93)90488-C . 25408172 .
• Johnson DW, Berg JN, Gallione CJ, McAllister KA, Warner JP, Helmbold EA, Markel DS, Jackson CE, Porteous ME, Marchuk DA . A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12 . Genome Research . 5 . 1 . 21–8 . August 1995 . 8717052 . 10.1101/gr.5.1.21 . free .
• Panchenko MP, Williams MC, Brody JS, Yu Q . Type I receptor serine-threonine kinase preferentially expressed in pulmonary blood vessels . The American Journal of Physiology . 270 . 4 Pt 1 . L547-58 . April 1996 . 8928814 . 10.1152/ajplung.1996.270.4.L547.
• Berg JN, Gallione CJ, Stenzel TT, Johnson DW, Allen WP, Schwartz CE, Jackson CE, Porteous ME, Marchuk DA . The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2 . American Journal of Human Genetics . 61 . 1 . 60–7 . July 1997 . 9245985 . 1715857 . 10.1086/513903 .
• Stockwell BR, Schreiber SL . Probing the role of homomeric and heteromeric receptor interactions in TGF-beta signaling using small molecule dimerizers . Current Biology . 8 . 13 . 761–70 . June 1998 . 9651680 . 10.1016/S0960-9822(98)70299-4 . 93779 . free . 1998CBio....8..761S .
• Lux A, Attisano L, Marchuk DA . Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1 . The Journal of Biological Chemistry . 274 . 15 . 9984–92 . April 1999 . 10187774 . 10.1074/jbc.274.15.9984 . free .
• Klaus DJ, Gallione CJ, Anthony K, Yeh EY, Yu J, Lux A, Johnson DW, Marchuk DA . Novel missense and frameshift mutations in the activin receptor-like kinase-1 gene in hereditary hemorrhagic telangiectasia. Mutations in brief no. 164. Online . Human Mutation . 12 . 2 . 137–138 . 2000 . 10694922 . 10.1002/(SICI)1098-1004(1998)12:2<137::AID-HUMU16>3.0.CO;2-J . free .
• Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E . Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis . Proceedings of the National Academy of Sciences of the United States of America . 97 . 6 . 2626–31 . March 2000 . 10716993 . 15979 . 10.1073/pnas.97.6.2626 . 2000PNAS...97.2626O . free .
• Abdalla SA, Pece-Barbara N, Vera S, Tapia E, Paez E, Bernabeu C, Letarte M . Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2 . Human Molecular Genetics . 9 . 8 . 1227–37 . May 2000 . 10767348 . 10.1093/hmg/9.8.1227 . free .
• Kjeldsen AD, Brusgaard K, Poulsen L, Kruse T, Rasmussen K, Green A, Vase P . Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families . American Journal of Medical Genetics . 98 . 4 . 298–302 . February 2001 . 11170071 . 10.1002/1096-8628(20010201)98:4<298::AID-AJMG1093>3.0.CO;2-K .
• 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 . The Journal of Biological Chemistry . 276 . 22 . 19495–502 . June 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 . The Journal of Biological Chemistry . 276 . 22 . 19332–9 . June 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 . The Journal of Biological Chemistry . 276 . 28 . 26542–9 . July 2001 . 11356828 . 10.1074/jbc.M100331200 . free .
• Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, Nichols WC, Morrell NW, Berg J, Manes A, McGaughran J, Pauciulo M, Wheeler L . Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia . The New England Journal of Medicine . 345 . 5 . 325–34 . August 2001 . 11484689 . 10.1056/NEJM200108023450503 . 2381/35988 . free .
• 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 . Molecular Pharmacology . 62 . 1 . 65–74 . July 2002 . 12065756 . 10.1124/mol.62.1.65 . 15185199 .
• Olivieri C, Mira E, Delù G, Pagella F, Zambelli A, Malvezzi L, Buscarini E, Danesino C . Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia . Journal of Medical Genetics . 39 . 7 . 39e–39 . July 2002 . 12114496 . 1735165 . 10.1136/jmg.39.7.e39 .
• Mo J, Fang SJ, Chen W, Blobe GC . Regulation of ALK-1 signaling by the nuclear receptor LXRbeta . The Journal of Biological Chemistry . 277 . 52 . 50788–94 . December 2002 . 12393874 . 10.1074/jbc.M210376200 . free .
• Lamouille S, Mallet C, Feige JJ, Bailly S . Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis . Blood . 100 . 13 . 4495–501 . December 2002 . 12453878 . 10.1182/blood.V100.13.4495 . free .
• Mitchell D, Pobre EG, Mulivor AW, Grinberg AV, Castonguay R, Monnell TE, Solban N, Ucran JA, Pearsall RS, Underwood KW, Seehra J, Kumar R . ALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growth . Molecular Cancer Therapeutics . 9 . 2 . 379–88 . February 2010 . 20124460 . 10.1158/1535-7163.MCT-09-0650 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Hereditary Hemorrhagic Telangiectasia

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. Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, Guttmacher AE, Jackson CE, Attisano L, Kucherlapati R, Porteous ME, Marchuk DA . Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2 . Nature Genetics . 13 . 2 . 189–95 . June 1996 . 8640225 . 10.1038/ng0696-189 . 21379604 .
3. Web site: Entrez Gene: ACVRL1 activin A receptor type II-like 1.
4. Olivieri C, Mira E, Delù G, Pagella F, Zambelli A, Malvezzi L, Buscarini E, Danesino C . Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia . Journal of Medical Genetics . 39 . 7 . 39e–39 . July 2002 . 12114496 . 1735165 . 10.1136/jmg.39.7.e39 .
5. Vandenbriele C, Peerlinck K, de Ravel T, Verhamme P, Vanassche T . Pulmonary arterio-venous malformations in a patient with a novel mutation in exon 10 of the ACVRL1 gene . Acta Clinica Belgica . 69 . 2 . 139–41 . April 2014 . 24724759 . 10.1179/0001551213Z.00000000012 . 35264961 .
6. Jones G, Robertson L, Harrison R, Ridout C, Vasudevan P . Somatic mosaicism in ACVRL1 with transmission to several offspring affected with severe pulmonary arterial hypertension . American Journal of Medical Genetics. Part A . 164A . 8 . 2121–3 . August 2014 . 24753439 . 10.1002/ajmg.a.36568 . 5417225 .
7. Kraehling JR, Chidlow JH, Rajagopal C, Sugiyama MG, Fowler JW, Lee MY, Zhang X, Ramírez CM, Park EJ, Tao B, Chen K, Kuruvilla L, Larriveé B, Folta-Stogniew E, Ola R, Rotllan N, Zhou W, Nagle MW, Herz J, Williams KJ, Eichmann A, Lee WL, Fernández-Hernando C, Sessa WC . Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells . Nature Communications . 7 . 13516 . November 2016 . 27869117 . 10.1038/ncomms13516 . 5121336. 2016NatCo...713516K .
8. Gupta S, Gill D, Pal SK, Agarwal N . Activin receptor inhibitors--dalantercept . Current Oncology Reports . 17 . 4 . 14 . 2015 . 25708802 . 10.1007/s11912-015-0441-5 . 22676858 .
9. Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, Martin W, Fornwald J, Lehr R, Harling J, Gaster L, Callahan JF, Olson BA . 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 . Molecular Pharmacology . 62 . 1 . 58–64 . July 2002 . 12065755 . 10.1124/mol.62.1.58 . 792324 .