PI 3-kinase, Akt and cell survival

Abstract

Phosphoinositide 3-OH kinase (PI 3-kinase) provides cells with a survival signal that allows them to withstand apoptotic stimuli. Many tumour cells display elevated levels of PI 3-kinase products as a result of deletion of the phosphatase PTEN, activation of Ras or expression of autocrine growth factors. As a result they are relatively resistant to apoptosis. The mechanisms for PI 3-kinase survival signalling are becoming clear. The principal mediator is Akt, a PI 3-kinase activated protein kinase. Akt has direct effects on the apoptosis machinery, for example targeting the pro-apoptotic Bcl-2 related protein, BAD. It also affects the transcriptional response to apoptotic stimuli, for example by acting on Forkhead factors and also influence the activity of the p53 family. In addition, novel connections between the metabolic effects of Akt and its control of survival have recently been made.

Introduction

Nearly 10 years ago it was recognised by Yao and Cooper that activation of phosphoinositide 3-OH kinase (PI 3-kinase) provided cells with a survival signal that allowed them to withstand apoptotic insults [1]. It subsequently rapidly became clear the PI 3-kinase pathway was one of the major anti-apoptotic pathways operating in cells, being switched on in response to activation of a wide range of trophic signals including soluble growth factors and attachment to extracellular matrix [2]. Several groups soon established that a major component of the survival signal provided by activation of PI 3-kinase was mediated by the Akt family of protein serine/threonine kinases, Akt1, Akt2 and Akt3, also known as PKBα, PKBβ and PKBγ [3], [4], [5], [6], [7]. The mechanisms by which PI 3-kinase and other regulators control the activity of Akt have been recently reviewed [8]. In this review, I will principally focus on the mechanisms by which Akt promotes cell survival.

An enormous amount of research has been conducted over the past 7 years into the molecular mechanisms whereby activation of the protein kinase activity of Akt results in protection of a wide range of cells from programmed cell death. The constitutive activation of Akt in many human tumours has held out the promise that this pathway may yield novel therapeutic targets for development of anti-cancer drugs, providing a further spur for this work. Investigations in this area can broadly be categorised into two approaches. One has been to investigate the consequences of Akt activation on the function of the apoptosis machinery. The other has been to attempt to identify physiological substrate proteins for Akt and to address whether they influence the control of apoptosis.