Regulation of inositol 5-phosphatase activity by the C2 domain of SHIP1 and SHIP2

Abstract

SH2-containing-inositol-5-phosphatases (SHIP1 and SHIP2) are key parts of the PI3K/AKT/mTOR signalling pathway. SHIPs dephosphorylate phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) to produce phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2). The balance between these two second messengers and related inositol- and phosphatidylinositol phosphates (PIPs) ultimately affects a wide number of cellular processes including inflammation, autophagy, cell migration, metabolism and cell growth.1,2 Therefore, it is not surprising that SHIPs have been implicated in many conditions, including a range of cancers,3-5 diabetes,6 hypertension,7 and graft versus host disease.8 Genome wide association studies and follow-up investigations have demonstrated a link between SNPs rs10933431 in intron 2 and rs35349669 in intron 10 of the INPP5D gene (SHIP1), increased expression of SHIP1, and increased risk of late-onset Alzheimer’s disease (LOAD) in Caucasians.9-11 The latter of these two mutations, on the other hand, does not appear to result in increased risk of LOAD in the Han Chinese population.12