title: Regulation of PI3K effector signalling in cancer by the phosphoinositide phosphatases.
abstract: Class I phosphoinositide 3-kinase (PI3K) generates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) at the plasma membrane in response to growth factors, activating a signalling cascade that regulates many cellular functions including cell growth, proliferation, survival, migration and metabolism. The PI3K pathway is commonly dysregulated in human cancer, and drives tumorigenesis by promoting aberrant cell growth and transformation. PtdIns(3,4,5)P3facilitates the activation of many pleckstrin homology (PH) domain-containing proteins including the serine/threonine kinase AKT. There are three AKT isoforms that are frequently hyperactivated in cancer through mutation, amplification or dysregulation of upstream regulatory proteins. AKT isoforms have converging and opposing functions in tumorigenesis. PtdIns(3,4,5)P3signalling is degraded and terminated by phosphoinositide phosphatases such as phosphatase and tensin homologue (PTEN), proline-rich inositol polyphosphate 5-phosphatase (PIPP) (INPP5J) and inositol polyphosphate 4-phosphatase type II (INPP4B). PtdIns(3,4,5)P3is rapidly hydrolysed by PIPP to generate phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), which is further hydrolysed by INPP4B to form phosphatidylinositol 3-phosphate (PtdIns3P). PtdIns(3,4)P2and PtdIns3Pare also important signalling molecules; PtdIns(3,4)P2together with PtdIns(3,4,5)P3are required for maximal AKT activation and PtdIns3Pactivates PI3K-dependent serum and glucocorticoid-regulated kinase (SGK3) signalling. Loss ofPten, PipporInpp4bexpression or function promotes tumour growth in murine cancer models through enhanced AKT isoform-specific signalling. INPP4B inhibits PtdIns(3,4)P2-mediated AKT activation in breast and prostate cancer; however, INPP4B expression is increased in acute myeloid leukaemia (AML), melanoma and colon cancer where it paradoxically promotes cell proliferation, transformation and/or drug resistance. This review will discuss how PTEN, PIPP and INPP4B distinctly regulate PtdIns(3,4,5)P3signalling downstream of PI3K and how dysregulation of these phosphatases affects cancer outcomes.
authors.affiliation: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Rodgers
authors.affiliation: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Ferguson
authors.affiliation: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Mitchell
authors.affiliation: Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia lisa.ooms@monash.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ooms
mesh_terms: D000818:Animals; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000072180:Phosphoinositide Phosphatases / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018129:Phosphatidylinositol Phosphates; D020033:Protein Isoforms; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000072180:Phosphoinositide Phosphatases
keywords: AKT; SGK3; cancer; phosphatidylinositol-3,4,5-trisphosphate; phosphoinositide 3-kinase; phosphoinositide phosphatases