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. It regulates the endosomal pathway and cytoskeletal dynamics using its GTPase-activating protein activity.

Structure

ARAP1 consists of Arf GAP, Rho GAP, Ankyrin repeat, RA, and five PH domains. 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.
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.

Function

ARAP1 was shown to exhibit GTPase-activating protein activity for Arf and Rho GTPases in vitro. 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 PIP3 in vitro. ARAP1 prefers Arf1 and Arf5 over Arf6 as substrate. The GAP activity exerted on Rho proteins is not dependent on phosphoinositides.
Association of ARAP1 with the Golgi complex and endosomes was observed. This association depends on the presence of phosphatidylinositol 3-phosphate and phosphatidylinositol 4-phosphate. There is conflicting research on the effect of ARAP1's level on the Golgi apparatus, as some report no effect on Golgi, while others report physiological changes. 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.
The Rho GAP activity of ARAP1 causes cell rounding and loss of stress fibers, while the Arf GAP activity causes the formation of filopodia. Furthermore, ARAP1 is implicated in the organization of the cytoskeleton, as it regulates the ring size of the circular dorsal ruffle and controls the actin dynamics and membrane traffic in osteoclasts.

Disease association

Genome-wide association studies in populations of European ancestry have identified nine SNP's on chromosome 11 that contributes to an independent as well as cumulative effect on the risk of developing type II diabetes mellitus. 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.