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 tumourigenesis by promoting aberrant cell growth and transformation. PtdIns(3,4,5)P3 facilitates the activation of many PH domain-containing proteins including the serine/threonine kinase AKT. There are three AKT isoforms which are frequently hyperactivated in cancer through mutation, amplification or dysregulation of upstream regulatory proteins. AKT isoforms have converging and opposing functions in tumourigenesis. PtdIns(3,4,5)P3 signalling is degraded and terminated by phosphoinositide phosphatases such as PTEN, PIPP (INPP5J) and INPP4B. PtdIns(3,4,5)P3 is rapidly hydrolysed by PIPP to generate PtdIns(3,4)P2, which is further hydrolysed by INPP4B to form PtdIns(3)P. PtdIns(3,4)P2 and PtdIns(3)P are also important signalling molecules; PtdIns(3,4)P2 together with PtdIns(3,4,5)P3 is required for maximal AKT activation and PtdIns(3)P activates PI3K-dependent SGK3 signalling. Loss of Pten , Pipp or Inpp4b expression 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 leukemia (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)P3 signalling downstream of PI3K and how dysregulation of these phosphatases impacts on cancer outcomes.
- phosphoinositide 3-kinase
- phosphoinositide phosphatases
- ©2017 The Author(s)
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