The phosphoinositide 5-phosphatase INPP5K: From gene structure to in vivo functions

Abstract

INPP5K (Inositol Polyphosphate 5-Phosphatase K, or SKIP (for Skeletal muscle and Kidney enriched Inositol Phosphatase) is a member of the phosphoinositide 5-phosphatases family. Its protein structure is comprised of a N-terminal catalytic domain which hydrolyses both PtdIns(4,5)P2 and PtdIns(3,4,5)P3, followed by a SKICH domain at the C-terminus which is responsible for protein-protein interactions and subcellular localization of INPP5K. Strikingly, INPP5K is mostly concentrated in the endoplasmic reticulum, although it is also detected at the plasma membrane, in the cytosol and the nucleus. Recently, mutations in INPP5K have been detected in patients with a rare form of autosomal recessive congenital muscular dystrophy with cataract, short stature and intellectual disability. INPP5K functions extend from control of insulin signaling, endoplasmic reticulum stress response and structural integrity, myoblast differentiation, cytoskeleton organization, cell adhesion and migration, renal osmoregulation, to cancer. The goal of this review is thus to summarize and comment recent and less recent data in the literature on INPP5K, in particular on the structure, expression, intracellular localization, interactions and functions of this specific member of the 5-phosphatases family.

Loss of INPP5K attenuates IP3-induced Ca2+ responses in the glioblastoma cell line U-251 MG cells

“…Members include Lowe oculocerebrorenal syndrome protein (OCRL), inositol polyphosphate 5-phosphatase B (INPP5B), SH2-containing inositol 5-phosphatase1/2 (SHIP1/2), synaptojanin1/2 (SYNJ1/2), inositol polyphosphate 5-phosphatase E (INPP5E), proline rich inositol polyphosphate 5-phosphatase (INPP5J) and inositol polyphosphate 5-phosphatase K (INPP5K) [1] . INPP5K can use two lipid substrates PI(4,5)P 2 and PI(3,4,5)P 3 to generate PI4P and PI(3,4)P 2 , respectively [2] . The human INPP5K is a 448 amino acid protein with an N-terminal catalytic domain and a INPP5K carboxy homology C-terminal domain responsible for protein-protein interactions as well as subcellular distribution of the phosphatase [2] .…”

“…INPP5K can use two lipid substrates PI(4,5)P 2 and PI(3,4,5)P 3 to generate PI4P and PI(3,4)P 2 , respectively [2] . The human INPP5K is a 448 amino acid protein with an N-terminal catalytic domain and a INPP5K carboxy homology C-terminal domain responsible for protein-protein interactions as well as subcellular distribution of the phosphatase [2] . Most recent studies have concluded PI(4,5)P 2 to be the preferred substrate of the phosphatase [3] , [4] , [5] , [6] , [7] .…”