ACVRL1

ACVRL1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2LCR, 3MY0, 4FAO
Identifiers
Aliases	ACVRL1, ACVRLK1, ALK-1, ALK1, HHT, HHT2, ORW2, SKR3, TSR-I, activin A receptor like type 1
External IDs	OMIM: 601284; MGI: 1338946; HomoloGene: 20058; GeneCards: ACVRL1; OMA:ACVRL1 - orthologs
Gene location (Human)
Chr.	Chromosome 12 (human)
End	51,923,361 bp
Gene location (Mouse)
Chr.	Chromosome 15 (mouse)
End	101,043,217 bp
RNA expression pattern
	Top expressed in
	right lung; ; upper lobe of left lung; ; tendon of biceps brachii; ; apex of heart; ; mucosa of transverse colon; ; left uterine tube; ; lower lobe of lung; ; right lobe of thyroid gland; ; subcutaneous adipose tissue; ; canal of the cervix;
	Top expressed in
	granulocyte; ; right lung; ; left lung; ; right lung lobe; ; left lung lobe; ; cardiac muscle tissue of left ventricle; ; extensor digitorum longus muscle; ; extraocular muscle; ; plantaris muscle; ; choroid plexus of fourth ventricle;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	transferase activity; nucleotide binding; protein kinase activity; activin binding; transforming growth factor beta-activated receptor activity; metal ion binding; kinase activity; protein serine/threonine kinase activity; transmembrane receptor protein serine/threonine kinase activity; protein binding; BMP receptor activity; ATP binding; protein kinase binding; transforming growth factor beta binding; transforming growth factor beta receptor activity, type I; activin receptor activity, type I; SMAD binding; growth factor binding;
Cellular component	integral component of membrane; membrane; integral component of plasma membrane; soma; dendrite; plasma membrane; cell surface; receptor complex; activin receptor complex;
Biological process	cellular response to transforming growth factor beta stimulus; negative regulation of cell adhesion; regulation of transcription, DNA-templated; positive regulation of endothelial cell differentiation; positive regulation of endothelial cell proliferation; blood vessel morphogenesis; negative regulation of blood vessel endothelial cell migration; lymphangiogenesis; regulation of DNA replication; phosphorylation; endothelial tube morphogenesis; retina vasculature development in camera-type eye; wound healing, spreading of epidermal cells; lymphatic endothelial cell differentiation; positive regulation of pathway-restricted SMAD protein phosphorylation; cellular response to BMP stimulus; negative regulation of endothelial cell differentiation; in utero embryonic development; blood vessel endothelial cell proliferation involved in sprouting angiogenesis; blood circulation; positive regulation of angiogenesis; venous blood vessel development; negative regulation of endothelial cell migration; negative regulation of endothelial cell proliferation; regulation of blood vessel endothelial cell migration; regulation of blood pressure; positive regulation of transcription, DNA-templated; protein phosphorylation; blood vessel remodeling; negative regulation of cell migration; transmembrane receptor protein serine/threonine kinase signaling pathway; negative regulation of cell growth; positive regulation of chondrocyte differentiation; angiogenesis; artery development; regulation of endothelial cell proliferation; positive regulation of BMP signaling pathway; transforming growth factor beta receptor signaling pathway; negative regulation of focal adhesion assembly; negative regulation of DNA biosynthetic process; signal transduction; negative regulation of cell population proliferation; blood vessel maturation; activin receptor signaling pathway; response to hypoxia; endocardial cushion to mesenchymal transition; endocardial cushion morphogenesis; negative regulation of gene expression; dorsal aorta morphogenesis; positive regulation of transcription by RNA polymerase II; BMP signaling pathway; pattern specification process;
	Sources:Amigo / QuickGO
Orthologs
	94
	11482
	ENSG00000139567
	ENSMUSG00000000530
	P37023
	Q61288
	NM_000020; NM_001077401
	NM_001277255; NM_001277257; NM_001277258; NM_001277259; NM_009612
	NP_000011; NP_001070869
	NP_001264184; NP_001264186; NP_001264187; NP_001264188; NP_033742
	Wikidata
View/Edit Human	View/Edit Mouse

Serine/threonine-protein kinase receptor R3 is an enzyme that in humans is encoded by the ACVRL1 gene.^[5]^[6]^[7]

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.^[7]

Pathology

Germline mutations of ACVRL1 are associated with:

hereditary hemorrhagic telangiectasia type 2 (Rendu-Osler-Weber syndrome 2)^[8]
Pulmonary arteriovenous malformations^[9]

Somatic mosaicism in ACVRL1 are associated with severe pulmonary arterial hypertension.^[10]

ACVRL1 directly interacts with low-density lipoprotein (LDL), which implies that it might initiate the early phases of atherosclerosis.^[11]

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.^[12]

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.^[13]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000139567 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000000530 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ten Dijke P, Ichijo H, Franzén P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K (October 1993). "Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity". Oncogene. 8 (10): 2879–87. PMID 8397373.
^ 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 (June 1996). "Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2". Nature Genetics. 13 (2): 189–95. doi:10.1038/ng0696-189. PMID 8640225. S2CID 21379604.
^ ^a ^b "Entrez Gene: ACVRL1 activin A receptor type II-like 1".
^ Olivieri C, Mira E, Delù G, Pagella F, Zambelli A, Malvezzi L, Buscarini E, Danesino C (July 2002). "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. doi:10.1136/jmg.39.7.e39. PMC 1735165. PMID 12114496.
^ Vandenbriele C, Peerlinck K, de Ravel T, Verhamme P, Vanassche T (April 2014). "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. doi:10.1179/0001551213Z.00000000012. PMID 24724759. S2CID 35264961.
^ Jones G, Robertson L, Harrison R, Ridout C, Vasudevan P (August 2014). "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. doi:10.1002/ajmg.a.36568. PMID 24753439. S2CID 5417225.
^ 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 (November 2016). "Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells". Nature Communications. 7: 13516. Bibcode:2016NatCo...713516K. doi:10.1038/ncomms13516. PMC 5121336. PMID 27869117.
^ Gupta S, Gill D, Pal SK, Agarwal N (2015). "Activin receptor inhibitors--dalantercept". Current Oncology Reports. 17 (4): 14. doi:10.1007/s11912-015-0441-5. PMID 25708802. S2CID 22676858.
^ 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 (July 2002). "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. doi:10.1124/mol.62.1.58. PMID 12065755. S2CID 792324.

External links

GeneReviews/NCBI/NIH/UW entry on Hereditary Hemorrhagic Telangiectasia
Human ACVRL1 genome location and ACVRL1 gene details page in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000139567 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000000530 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid8397373-5] ten Dijke P, Ichijo H, Franzén P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K (October 1993). "Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity". Oncogene. 8 (10): 2879–87. PMID 8397373.

[pmid8640225-6] 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 (June 1996). "Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2". Nature Genetics. 13 (2): 189–95. doi:10.1038/ng0696-189. PMID 8640225. S2CID 21379604.

[entrez-7] "Entrez Gene: ACVRL1 activin A receptor type II-like 1".

[pmid12114496-8] Olivieri C, Mira E, Delù G, Pagella F, Zambelli A, Malvezzi L, Buscarini E, Danesino C (July 2002). "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. doi:10.1136/jmg.39.7.e39. PMC 1735165. PMID 12114496.

[pmid24724759-9] Vandenbriele C, Peerlinck K, de Ravel T, Verhamme P, Vanassche T (April 2014). "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. doi:10.1179/0001551213Z.00000000012. PMID 24724759. S2CID 35264961.

[Jones_2014-10] Jones G, Robertson L, Harrison R, Ridout C, Vasudevan P (August 2014). "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. doi:10.1002/ajmg.a.36568. PMID 24753439. S2CID 5417225.

[11] 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 (November 2016). "Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells". Nature Communications. 7: 13516. Bibcode:2016NatCo...713516K. doi:10.1038/ncomms13516. PMC 5121336. PMID 27869117.

[pmid25708802-12] Gupta S, Gill D, Pal SK, Agarwal N (2015). "Activin receptor inhibitors--dalantercept". Current Oncology Reports. 17 (4): 14. doi:10.1007/s11912-015-0441-5. PMID 25708802. S2CID 22676858.

[Grygielko2002-13] 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 (July 2002). "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. doi:10.1124/mol.62.1.58. PMID 12065755. S2CID 792324.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)