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Science 317 (5835): 239-242

Copyright © 2007 by the American Association for the Advancement of Science

Mechanism of Two Classes of Cancer Mutations in the Phosphoinositide 3-Kinase Catalytic Subunit

Nabil Miled,1*{dagger} Ying Yan,2* Wai-Ching Hon,1 Olga Perisic,1 Marketa Zvelebil,3 Yuval Inbar,4 Dina Schneidman-Duhovny,4 Haim J. Wolfson,4 Jonathan M. Backer,2{ddagger} Roger L. Williams1{ddagger}

Abstract: Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3K{alpha}, with oncogenic mutations identified in both the p110{alpha} catalytic and the p85{alpha} regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110{alpha} domains—the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110{alpha} in a complex with the p85{alpha} inter–Src homology 2 (inter-SH2) domain shows that oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. We also examined helical domain mutations and found that the Glu545 to Lys545 (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer.

1 Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
2 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY10461, USA.
3 Ludwig Institute for Cancer Research, University College London, London W1W 7BS, UK.
4 School of Computer Science, The Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel.

* These authors contributed equally to this work.

{dagger} Present address: Laboratoire de Biochimie et de Génie Enzymatique des Lipases, Ecole Nationale d'Ingenieurs Sfax, Route Soukra BPW, 3038 Sfax, Tunisia.

{ddagger} To whom correspondence should be addressed. E-mail: rlw{at}mrc-lmb.cam.ac.uk (R.L.W.); backer{at}aecom.yu.edu (J.M.B.)

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