Two distinct phosphoinositide 3-kinases mediate polypeptide growth factor-stimulated PKB activation

Abstract

Eight human isoforms of phosphoinositide 3-kinases (PI3Ks) exist, but their individual functions remain poorly understood. Here, we show that different human small cell lung carcinoma (SCLC) cell lines overexpress distinct subsets of class IA and II PI3Ks, which results in striking differences in the signalling cascades activated by stem cell factor (SCF). Over-expression of class IA p85/p110α in SCLC cells increased SCF-stimulated protein kinase B (PKB) activation and cell growth, but did not affect extracellular signal-regulated kinase (Erk) or glycogen synthase kinase-3 (GSK-3). This effect was selective, since it was not observed in SCLC cell lines over-expressing p85/p110β or p85/p110δ. The SCF receptor associated with both class IA p85 and class II PI3KC2β, and both enzymes contributed to SCF-stimulated PKB activity. A dominant-negative PI3KC2β blocked both PKB activation and SCLC cell growth in response to SCF. Together our data provide novel insights into the specificity and functional significance of PI3K signalling in human cancer.