Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases

The phosphoinositide 3-kinase (PI3K) generated lipid signals, PtdIns(3,4,5) P 3 and PtdIns(3,4) P 2, are both required for the maximal activation of the serine/threonine kinase proto-oncogene Akt. The inositol polyphosphate 5-phosphatases (5-phosphatases) hydrolyse the 5-position phosphate from the inositol head group of PtdIns(3,4,5) P 3 to yield PtdIns(3,4) P 2. Extensive work has revealed several 5-phosphatases inhibit PI3K-driven Akt signalling, by decreasing PtdIns(3,4,5) P 3 despite increasing cellular levels of PtdIns(3,4) P 2. The roles that 5-phosphatases play in suppressing cell proliferation and transformation are slow to emerge; however, the 5-phosphatase PIPP [proline-rich inositol polyphosphate 5-phosphatase; inositol polyphosphate 5-phosphatase ( INPP5J )] has recently been identified as a putative tumour suppressor in melanoma and breast cancer and SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase 1] inhibits haematopoietic cell proliferation. INPP5E regulates cilia stability and INPP5E mutations have been implicated ciliopathy syndromes. This review will examine 5-phosphatase regulation of PI3K/Akt signalling, focussing on the role PtdIns(3,4,5) P 3 5-phosphatases play in developmental diseases and cancer. * 3AC, : 3-a-aminocholestane; 5-phosphatases, : inositol polyphosphate 5-phosphatases; AURKA, : aurora kinase A; BJAB, : human B-cell lymphoma cell line; BMMC, : bone marrow-derived mast cells; CHO, : Chinese hamster ovary; EGF, : epidermal growth factor; ENU, : N -ethyl- N -nitrosourea; ER, : estrogen receptor; FoxO, : forkhead box, class O; GLUT4, : glucose transporter type 4; Gpr161, : G-protein-coupled receptor 161; HEK, : human embryonic kidney; IGF-1, : insulin-like growth factor-1; IL-3, : interleukin-3; LPS, : lipopolysaccharide; MEF, : mouse embryonic fibroblast; MM, : multiple myeloma; mTORC, : mammalian target of rapamycin complex; NFAT, : nuclear factor of activated T cells; OCRL, : oculocerebrorenal syndrome of Lowe; Pak1, : P21-activated kinase 1; PDK1, : phosphoinositide-dependent kinase 1; PH, : pleckstrin homology; 1PIE, : (2-phenyl-benzo[ h ]quinolin-4-yl)-[2]piperidyl-methanol hydrochloride; 2PIQ, : 1-[(chlorophenyl)methyl]-2-methyl-5-(methylthio)-1H-indole-3-ethanamine hydrochloride; 6PTQ, : (2-adamantan-1-yl-6,8-dichloro-quinolin-4-yl)-pyridin-2-yl-methanol hydrochloride; PI3K, : phosphoinositide 3-kinase; PIPP, : proline-rich inositol polyphosphate 5-phosphatase; PRAS40, : proline-rich Akt substrate of 40 kDa; PTEN, : phosphatase and tensin homologue deleted on chromosome 10; PyMT, : polyoma middle T; Rheb, : Ras homologue enriched in brain; RhoGAP, : Rho GTP-ase activating protein; SAG, : smoothened agonist; Shh, : sonic hedgehog; SHIP, : SH2-containing inositol phosphatase; SKICH, : SKIP carboxy homology; SKIP, : skeletal muscle- and kidney-enriched inositol phosphatase; TNFα, : tumour necrosis factor α; TSC, : tuberous sclerosis; TULP3, : Tubby-like protein 3