ACVR1

ACVR1
Struktur yang tersedia
PDB	Pencarian Ortolog: PDBe RCSB
Daftar kode id PDB
	3H9R, 3MTF, 3OOM, 3Q4U, 4BGG, 4C02, 4DYM
Pengidentifikasi
Alias	ACVR1, ACTRI, ACVR1A, ACVRLK2, ALK2, FOP, SKR1, TSRI, activin A receptor type 1
ID eksternal	OMIM: 102576 MGI: 87911 HomoloGene: 7 GeneCards: ACVR1
Lokasi gen (Tikus)
Kr.	Kromosom 2 (tikus)
Akhir	58,457,169 bp
Ontologi gen
Fungsi molekuler	• transferase activity; • protein kinase activity; • activin receptor activity, type I; • nucleotide binding; • homodimerisasi protein; • growth factor binding; • activin binding; • metal ion binding; • kinase activity; • peptide hormone binding; • protein serine/threonine kinase activity; • transmembrane receptor protein serine/threonine kinase activity; • transforming growth factor beta receptor activity, type I; • GO:0001948, GO:0016582 Ikatan protein plasma; • ATP binding; • transforming growth factor beta binding; • SMAD binding; • transforming growth factor beta-activated receptor activity; • BMP receptor activity;
Komponen seluler	• komponen integral membran; • membran; • apical part of cell; • integral component of plasma membrane; • activin receptor complex; • receptor complex;
Proses biologis	• germ cell development; • pathway-restricted SMAD protein phosphorylation; • positive regulation of bone mineralization; • Fosforilasi; • positive regulation of cell migration; • mesoderm formation; • gastrulation with mouth forming second; • negative regulation of extrinsic apoptotic signaling pathway; • endocardial cushion cell fate commitment; • cellular response to BMP stimulus; • in utero embryonic development; • positive regulation of determination of dorsal identity; • mitral valve morphogenesis; • smooth muscle cell differentiation; • BMP signaling pathway; • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated; • protein phosphorylation; • negative regulation of activin receptor signaling pathway; • heart development; • determination of left/right symmetry; • positive regulation of osteoblast differentiation; • transmembrane receptor protein serine/threonine kinase signaling pathway; • acute inflammatory response; • Gastrulasi; • embryonic heart tube morphogenesis; • neural crest cell migration; • cardiac muscle cell fate commitment; • branching involved in blood vessel morphogenesis; • negative regulation of signal transduction; • regulation of ossification; • peptidyl-threonine phosphorylation; • mesoderm development; • transforming growth factor beta receptor signaling pathway; • pharyngeal system development; • activin receptor signaling pathway; • outflow tract septum morphogenesis; • atrioventricular valve morphogenesis; • endocardial cushion morphogenesis; • endocardial cushion fusion; • atrial septum primum morphogenesis; • positive regulation of pathway-restricted SMAD protein phosphorylation; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • ventricular septum morphogenesis; • BMP signaling pathway involved in heart development; • positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation; • G1/S transition of mitotic cell cycle; • pattern specification process;
	Sumber:Amigo / QuickGO
Ortolog
	90
	11477
	ENSG00000115170
	ENSMUSG00000026836
	Q04771
	P37172
NM_001105; NM_001111067; NM_001347663; NM_001347664; NM_001347665;
	NM_001347666; NM_001347667
	NM_001110204; NM_001110205; NM_007394; NM_001355048; NM_001355049
NP_001096; NP_001104537; NP_001334592; NP_001334593; NP_001334594;
	NP_001334595; NP_001334596
	NP_001103674; NP_001103675; NP_031420; NP_001341977; NP_001341978
	Wikidata
Lihat/Sunting Manusia	Lihat/Sunting Tikus

Reseptor Aktivin, tipe I (ACVR1) adalah protein yang pada manusia disandi oleh gen ACVR1; juga dikenal sebagai ALK-2 (activin receptor like kinase-2).^[4] ACVR1 telah dikaitkan dengan daerah kromosom 2q23-24.^[5] Protein ini penting dalam jalur protein morfogenik tulang (bone morphogenic protein, BMP) yang bertanggung jawab untuk pengembangan dan perbaikan sistem kerangka. Sementara model knock-out dengan gen ini sedang diteliti, gen ACVR1 telah dikaitkan dengan Fibrodysplasia Ossificans Progressiva, suatu penyakit yang ditandai dengan pembentukan tulang heterotopik di seluruh tubuh.^[5]

Fungsi

Aktivin adalah faktor pertumbuhan dan faktor diferensiasi dimerik yang termasuk dalam superfamili TGF-beta dari protein pensinyalan terkait secara struktural. Aktivin mengirimkan sinyal melalui kompleks heteromerik dari reseptor serin kinase yang mencakup setidaknya dua reseptor tipe I (I dan IB) dan dua reseptor tipe II (II dan IIB). Reseptor-reseptor ini merupakan protein transmembran, terdiri dari domain ekstraseluler pengikat ligan dengan daerah kaya sistein, domain transmembran, dan domain sitoplasma dengan prediksi spesifik serin/threonine. Reseptor tipe I sangat penting untuk pensinyalan; dan reseptor tipe II diperlukan untuk mengikat ligan dan untuk ekspresi reseptor tipe I. Reseptor tipe I dan II membentuk kompleks stabil setelah pengikatan ligan, menghasilkan fosforilasi reseptor tipe I oleh reseptor tipe II. Gen ini menyandi reseptor aktivin tipe I yang menandakan respons transkripsional tertentu bersamaan dengan reseptor aktivin tipe II.^[6]

Pensinyalan

ACVR1 mentransduksi sinyal dari BMP. BMP mengikat ACVR2A/ACVR2B atau BMPR2 dan kemudian membentuk kompleks dengan ACVR1. Kemudian reseptor merekrut R-SMAD SMAD1, SMAD2, SMAD3, atau SMAD6.^[7]

Signifikansi klinis

Mutasi pada gen ACVR1 (= ALK2) bertanggung jawab atas penyakit langka pembentukan tulang heterotopik (ekstraskeletal), fibrodysplasia ossificans progressiva.^[8]^[9] ACVR1 menyandi reseptor aktivin tipe-1, suatu reseptor BMP tipe-1. Mutasi ACVR1R206H menyebabkan protein ACVR1 memiliki asam amino histidin yang menggantikan (substitusi) asam amino arginin pada posisi 206.^[10] Hal ini menyebabkan protein ALK2 berubah dalam domain aktivasi protein glisin-serin kritis yang akan menyebabkan protein mengikat ligan penghambatnya (FKBP12) kurang erat, dan mengaktifkan protein spesifik jalur SMAD lebih efektif daripada biasanya.^[5] Hasilnya adalah jalur BMP akan terpicu terus-menerus, dan tulang akan terbentuk di jaringan lunak di seluruh tubuh. Hal ini menyebabkan sel endotelial berubah menjadi sel punca mesenkim dan kemudian menjadi tulang.^[11]

Mutasi pada gen ACVR1 juga dikaitkan dengan kanker, terutama pontine glioma intrinsik (diffuse intrinsic pontine glioma, DIPG).^[12]^[13]^[14]

Referensi

^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000026836 - 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.
^ "Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity". Oncogene. 8 (10): 2879–87. October 1993. PMID 8397373.
^ ^a ^b ^c Pignolo, Robert J. (June 2013). "Fibrodysplasia Ossificans Progressiva: Diagnosis, Management, and Therapeutic Horizons". Pediatr Endocrinol Rev.
^ "Entrez Gene: ACVR1 (activin A receptor, type I)".
^ "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. doi:10.1124/mol.62.1.65. PMID 12065756.
^ "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva". Nature Genetics. 38 (5): 525–7. May 2006. doi:10.1038/ng1783. PMID 16642017.
^ Haupt, Julia; Stanley, Alexandra; McLeod, Claire M.; Cosgrove, Brian D.; Culbert, Andria L.; Wang, Linda; Mourkioti, Foteini; Mauck, Robert L.; Shore, Eileen M. (2019-01-01). "ACVR1R206H FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification". Molecular Biology of the Cell. 30 (1): 17–29. doi:10.1091/mbc.E18-05-0311. ISSN 1939-4586. PMC 6337906 . PMID 30379592.
^ "News Release of FOP's Cause". Diarsipkan dari versi asli tanggal 2012-01-13. Diakses tanggal 2012-02-29.
^ "ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation". Journal of Bone and Mineral Research. 25 (6): 1208–15. June 2010. doi:10.1359/jbmr.091110. PMID 19929436.
^ "Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma". Nature Genetics. 46 (5): 457–61. May 2014. doi:10.1038/ng.2925. PMC 4018681 . PMID 24705252.
^ "Cure Brain Cancer - News - Multiple Breakthroughs in Childhood Brain Cancer DIPG". Cure Brain Cancer Foundation. Diarsipkan dari versi asli tanggal 2020-08-12. Diakses tanggal 2019-02-07.
^ "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations". Nature Genetics. 46 (5): 451–6. May 2014. doi:10.1038/ng.2936. PMC 3997489 . PMID 24705254.

[refGRCm38Ensembl-1] GRCm38: Ensembl release 89: ENSMUSG00000026836 - Ensembl, May 2017

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

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

[pmid8397373-4] "Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity". Oncogene. 8 (10): 2879–87. October 1993. PMID 8397373.

[:0-5] Pignolo, Robert J. (June 2013). "Fibrodysplasia Ossificans Progressiva: Diagnosis, Management, and Therapeutic Horizons". Pediatr Endocrinol Rev.

[6] "Entrez Gene: ACVR1 (activin A receptor, type I)".

[pmid12065756-7] "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. doi:10.1124/mol.62.1.65. PMID 12065756.

[ACVR1-8] "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva". Nature Genetics. 38 (5): 525–7. May 2006. doi:10.1038/ng1783. PMID 16642017.

[9] Haupt, Julia; Stanley, Alexandra; McLeod, Claire M.; Cosgrove, Brian D.; Culbert, Andria L.; Wang, Linda; Mourkioti, Foteini; Mauck, Robert L.; Shore, Eileen M. (2019-01-01). "ACVR1R206H FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification". Molecular Biology of the Cell. 30 (1): 17–29. doi:10.1091/mbc.E18-05-0311. ISSN 1939-4586. PMC 6337906 . PMID 30379592.

[10] "News Release of FOP's Cause". Diarsipkan dari versi asli tanggal 2012-01-13. Diakses tanggal 2012-02-29.

[11] "ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation". Journal of Bone and Mineral Research. 25 (6): 1208–15. June 2010. doi:10.1359/jbmr.091110. PMID 19929436.

[12] "Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma". Nature Genetics. 46 (5): 457–61. May 2014. doi:10.1038/ng.2925. PMC 4018681 . PMID 24705252.

[urlCure_Brain_Cancer_-_News_-_Multiple_Breakthroughs_in_Childhood_Brain_Cancer_DIPG-13] "Cure Brain Cancer - News - Multiple Breakthroughs in Childhood Brain Cancer DIPG". Cure Brain Cancer Foundation. Diarsipkan dari versi asli tanggal 2020-08-12. Diakses tanggal 2019-02-07.

[pmid24705254-14] "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations". Nature Genetics. 46 (5): 451–6. May 2014. doi:10.1038/ng.2936. PMC 3997489 . PMID 24705254.

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