Two distinct phosphoinositide 3-kinases mediate polypeptide growth factor-stimulated PKB activation.
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 I(A) and II PI3Ks, which results in striking differences in the signalling cascades activated by stem cell factor (SCF). Over expression of class I(A) p85/p110alpha 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 overexpressing p85/p110beta or p85/p110delta. The SCF receptor associated with both class I(A) p85 and class II PI3KC2beta, and both enzymes contributed to SCF-stimulated PKB activity. A dominant-negative PI3KC2beta 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.
D000818:Animals; D019556:COS Cells; D018288:Carcinoma, Small Cell; D002460:Cell Line; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D006133:Growth Substances; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins