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Molecular and Cellular Biology, February 2004, p. 966-975, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.966-975.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Regulation of Phosphoinositide 3-Kinase by Its Intrinsic Serine Kinase Activity In Vivo

Lazaros C. Foukas,1,{dagger} Caroline A. Beeton,1 Jorgen Jensen,2 Wayne A. Phillips,3 and Peter R. Shepherd1*

Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom,1 Department of Physiology, National Institute of Occupational Health, 0033 Oslo, Norway,2 Peter MacCallum Cancer Institute, Melbourne, Victoria 8006, Australia3

Received 19 May 2003/ Returned for modification 26 June 2003/ Accepted 3 November 2003

One potentially important mechanism for regulating class Ia phosphoinositide 3-kinase (PI 3-kinase) activity is autophosphorylation of the p85{alpha} adapter subunit on Ser608 by the intrinsic protein kinase activity of the p110 catalytic subunit, as this downregulates the lipid kinase activity in vitro. Here we investigate whether this phosphorylation can occur in vivo. We find that p110{alpha} phosphorylates p85{alpha} Ser608 in vivo with significant stoichiometry. However, p110ß is far less efficient at phosphorylating p85{alpha} Ser608, identifying a potential difference in the mechanisms by which these two isoforms are regulated. The p85{alpha} Ser608 phosphorylation was increased by treatment with insulin, platelet-derived growth factor, and the phosphatase inhibitor okadaic acid. The functional effects of this phosphorylation are highlighted by mutation of Ser608, which results in reduced lipid kinase activity and reduced association of the p110{alpha} catalytic subunit with p85{alpha}. The importance of this phosphorylation was further highlighted by the finding that autophosphorylation on Ser608 was impaired, while lipid kinase activity was increased, in a p85{alpha} mutant recently discovered in human tumors. These results provide the first evidence that phosphorylation of Ser608 plays a role as a shutoff switch in growth factor signaling and contributes to the differences in functional properties of different PI 3-kinase isoforms in vivo.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom. Phone: 44 20 7679 4482. Fax: 44 20 7679 7193. E-mail: p.shepherd{at}biochem.ucl.ac.uk.

{dagger} Present address: Ludwig Institute for Cancer Research, London W1W 7BS, United Kingdom.

Molecular and Cellular Biology, February 2004, p. 966-975, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.966-975.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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