PI 3-kinase,Akt/PKB and Ras signalling pathways involved in the control of cell survival

摘要

Phosphatidylinositol (PI) is a major phospholipid component of the plasma membrane. The inositol head group can be phosphorylated at several different positions, giving rise to a number of multiply phosphorylated species. PI 3-kinase was originally identified some fifteen years ago as an activity associated with certain tyrosine kinases that could phosphorylate PI at the 3' position. PI 3-kinase activity is activated in response to a very wide range of extracellular stimuli. Many different forms of PI 3-kinase have subsequently been identified and characterised. They are all related, but fall into three families. Type I PI 3-kinases are thought to be the major mitogen responsive activities: they are made up of catalytic subunits, usually about 110 kDa in size, and regulatory subunits. In the case of type IA PI 3-kinases, the catalytic subunits p110alpha, beta and delta associate with regulatory subunits (p85) that have two SH2 and one SH3 domains, through which they interact with other signalling proteins, in particular upstream activated tyrosine phosphorylated receptors and docking proteins. Type IB PI 3-kinases (p110gamma) have unrelated regulatory subunits through which they interact with G protein betagamma subunits. In this way type IA PI 3-kinases are activated following stimulation of tyrosine kinase coupled receptors and type IB following stimulation of G protein coupled receptors. In addition, both forms possess sites through which they interact with activated Ras proteins, also resulting in stimulation of PI 3-kinase activity.