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  • The EMBO Journal (2002) 21, 5097 - 5108
  • doi:10.1093/emboj/cdf512

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

Alexandre Arcaro1, Umme K. Khanzada1, Bart Vanhaesebroeck2,3, Teresa D. Tetley4, Michael D. Waterfield2,3 and Michael J. Seckl1

  1. Lung Cancer Biology Group, Division of Medicine, Imperial College Faculty of Medicine, Du Cane Road, London W12 0NN, UK
  2. Ludwig Institute for Cancer Research, Royal Free and University College Medical School, Riding House Street, London W1W 7BS, UK
  3. Department of Biochemistry and Molecular Biology, Gower Street, London WC1E 6BT, UK
  4. Lung Cell Biology, National Heart and Lung Institute, Imperial College Faculty of Medicine, Dovehouse Street, London SW3 6LY, UK

Correspondence to:

Alexandre Arcaro, E-mail: a.arcaro@ic.ac.uk

Received 15 February 2002; Accepted 7 August 2002; Revised 2 July 2002

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/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 IA 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.

  • Keywords:

    • cell growth,
    • c-Kit,
    • PI3K,
    • PKB,
    • SCLC