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PNAS 103 (5): 1289-1294

Copyright © 2006 by the National Academy of Sciences.


Oncogenic transformation induced by the p110beta, -{gamma}, and -{delta} isoforms of class I phosphoinositide 3-kinase

Sohye Kang*, Adam Denley*, Bart Vanhaesebroeck{dagger},{ddagger}, and Peter K. Vogt*,§

*Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC 239, La Jolla, CA 92037; {dagger}Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, United Kingdom; and {ddagger}Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom

Contributed by Peter K. Vogt, December 13, 2005

Abstract: Class I phosphoinositide 3-kinase contains four isoforms of the catalytic subunit, p110{alpha}, -beta, -{gamma}, and -{delta}. At physiological levels of expression, the wild-type p110{alpha} isoform lacks oncogenic potential, but gain-of-function mutations and overexpression of p110{alpha} are correlated with oncogenicity. The p110beta, -{gamma}, and -{delta} isoforms induce transformation of cultured cells as wild-type proteins. This oncogenic potential requires kinase activity and can be suppressed by the target of rapamycin inhibitor rapamycin. The p110{delta} isoform constitutively activates the Akt signaling pathway; p110{gamma} activates Akt only in the presence of serum. The isoforms differ in their requirements for upstream signaling. The transforming activity of the p110{gamma} isoform depends on rat sarcoma viral oncogene homolog (Ras) binding; preliminary data suggest the same for p110beta and indicate Ras-independent oncogenic potential of p110{delta}. The surprising oncogenic potential of the wild-type non-{alpha} isoforms of class I phosphoinositide 3-kinase may explain the dearth of cancer-specific mutations in these proteins, because these non-{alpha} isoforms could contribute to the oncogenic phenotype of the cell by differential expression.

Key Words: Akt

Author contributions: S.K. and P.K.V. designed research; S.K. and A.D. performed research; B.V. contributed new reagents/analytic tools;

Conflict of interest statement: No conflicts declared.

Abbreviations: CEF, chicken embryo fibroblasts; PI3K, phosphoinositide 3-kinase; RCAS, replication-competent avian leukosis virus with splice acceptor; TOR, target of rapamycin.

§ To whom correspondence should be addressed. E-mail: pkvogt{at}

© 2006 by The National Academy of Sciences of the USA

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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