ARAP1
Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 1 is a protein that in humans is encoded by the ARAP1 gene.[5] It regulates the endosomal pathway and cytoskeletal dynamics using its GTPase-activating protein activity.[6][7]
Structure
ARAP1 consists of Arf GAP, Rho GAP, Ankyrin repeat, RA, and five PH domains.[6] In Homo sapiens, ARAP1 has a length of 1450 amino acids and a molecular weight of 162kDa. Seven alternatively spliced human isoforms have been reported.[8]
Northern blot was used to infer the presence of ARAP1 in the following tissues: brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung, PBLC, adrenal gland, bladder, bone marrow, lymph node, mammary gland, prostate, spinal cord, stomach, thyroid, trachea, uterus.[6]
Function
ARAP1 was shown to exhibit GTPase-activating protein (GAP) activity for Arf and Rho GTPases in vitro.[6] ARAP1's activity on Arf proteins is stimulated by phosphoinositides, with PI(3,4)P2 and PI(3,4,5)P3 showing the strongest effect. The PH-1 domain is the only domain that binds PI(3,4,5)P3 in vitro.[9] ARAP1 prefers Arf1 and Arf5 over Arf6 as substrate. The GAP activity exerted on Rho proteins is not dependent on phosphoinositides.[6]
Association of ARAP1 with the Golgi complex and endosomes was observed.[9] This association depends on the presence of phosphatidylinositol 3-phosphate (endosomes) and phosphatidylinositol 4-phosphate (Golgi). There is conflicting research on the effect of ARAP1's level on the Golgi apparatus, as some report no effect on Golgi,[9] while others report physiological changes.[6] The endosomal pathway experiences differences dependent on ARAP1's abundance. Decreased ARAP1 levels accelerates endocytosis of epidermal growth factor receptor by reducing the available amount of Arf-GDP.[9][10]
The Rho GAP activity of ARAP1 causes cell rounding and loss of stress fibers,[6][9] while the Arf GAP activity causes the formation of filopodia.[6] Furthermore, ARAP1 is implicated in the organization of the cytoskeleton, as it regulates the ring size of the circular dorsal ruffle[7] and controls the actin dynamics and membrane traffic in osteoclasts.[11]
Disease association
Genome-wide association studies in populations of European ancestry have identified nine SNP's (single nuclear polymorphisms) on chromosome 11 that contributes to an independent as well as cumulative effect on the risk of developing type II diabetes mellitus.[12] CENTD2 is significantly associated with decreased glucose-stimulated insulin release and increased plasma glucose values, suggesting that an impaired pancreatic beta cell function is the mediator to the diabetogenic effect of this locus. [13]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000186635 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032812 – 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.
- ^ "Entrez Gene: CENTD2 centaurin, delta 2".
- ^ a b c d e f g h Miura K, Jacques KM, Stauffer S, Kubosaki A, Zhu K, Hirsch DS, et al. (2002), "ARAP1", Molecular Cell, 9 (1): 109–119, doi:10.1016/S1097-2765(02)00428-8, PMID 11804590
- ^ a b Hasegawa J, Tsujita K, Takenawa T, Itoh T (2012), "ARAP1 regulates the ring size of circular dorsal ruffles through Arf1 and Arf5", Molecular Biology of the Cell, 23 (13): 2481–2489, doi:10.1091/mbc.E12-01-0017, PMC 3386212, PMID 22573888
- ^ "ARAP1_HUMAN". Retrieved 2026-01-31.
- ^ a b c d e Daniele T, Di Tullio G, Santoro M, Turacchio G, De Matteis MA (2008), "ARAP1 Regulates EGF Receptor Trafficking and Signalling", Traffic, 9 (12): 2221–2235, doi:10.1111/j.1600-0854.2008.00823.x, PMID 18764928
- ^ Yoon H, Lee J, Randazzo PA (2008), "ARAP1 Regulates Endocytosis of EGFR", Traffic, 9 (12): 2236–2252, doi:10.1111/j.1600-0854.2008.00839.x, PMC 2959122, PMID 18939958
- ^ Segeletz S, Danglot L, Galli T, Hoflack B (2018), "ARAP1 Bridges Actin Dynamics and AP-3-Dependent Membrane Traffic in Bone-Digesting Osteoclasts", iScience, 6: 199–211, doi:10.1016/j.isci.2018.07.019, PMC 6137390, PMID 30240610
- ^ Qian Y, Dong M, Lu F, Li H, Jin G, Hu Z, et al. (2015-05-15). "Joint effect of CENTD2 and KCNQ1 polymorphisms on the risk of type 2 diabetes mellitus among Chinese Han population". Molecular and Cellular Endocrinology. 407: 46–51. doi:10.1016/j.mce.2015.02.026. ISSN 0303-7207. PMID 25749274.
- ^ Nielsen T, Sparsø T, Grarup N, Jørgensen T, Pisinger C, Witte DR, et al. (May 2011). "Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose-stimulated insulin release". Diabetologia. 54 (5): 1052–1056. doi:10.1007/s00125-011-2054-3. ISSN 1432-0428. PMID 21267535.
External links
- Human ARAP1 genome location and ARAP1 gene details page in the UCSC Genome Browser.
Further reading
- Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (June 2002). "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Research. 9 (3): 99–106. CiteSeerX 10.1.1.500.923. doi:10.1093/dnares/9.3.99. PMID 12168954.
- Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, et al. (October 1998). "Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 5 (5): 277–286. doi:10.1093/dnares/5.5.277. PMID 9872452.
- Krugmann S, Anderson KE, Ridley SH, Risso N, McGregor A, Coadwell J, et al. (January 2002). "Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices". Molecular Cell. 9 (1): 95–108. doi:10.1016/S1097-2765(02)00434-3. PMID 11804589.
- Miura K, Jacques KM, Stauffer S, Kubosaki A, Zhu K, Hirsch DS, et al. (January 2002). "ARAP1: a point of convergence for Arf and Rho signaling". Molecular Cell. 9 (1): 109–119. doi:10.1016/S1097-2765(02)00428-8. PMID 11804590.
- Ahn J, Chung KS, Kim DU, Won M, Kim L, Kim KS, et al. (November 2004). "Systematic identification of hepatocellular proteins interacting with NS5A of the hepatitis C virus". Journal of Biochemistry and Molecular Biology. 37 (6): 741–748. doi:10.5483/bmbrep.2004.37.6.741. PMID 15607035.
- Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, et al. (September 2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–968. Bibcode:2005Cell..122..957S. doi:10.1016/j.cell.2005.08.029. hdl:11858/00-001M-0000-0010-8592-0. PMID 16169070. S2CID 8235923.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, et al. (November 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–648. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.