University of California

Chiron Corporation

Anke Klippel

Lewis T Williams

W Michael Kavanaugh

Stephen David Harrison

Polynucleotide constructs encoding growth factor independent catalytically active membrane targeted PI 3-kinase mutants useful for therapeutic and research purposes are described. In addition, a method for using the polynucleotide constructs to screen for inhibitors of PI 3-kinase, a method for making 3&prime; phosphorylated inositol phospholipids, methods of reducing cell death after trauma, and methods of overcoming insulin resistance are described.

PI 3-kinase fusion mutants and uses thereof

The invention provides a method of producing a constitutively active phosphatidylinositol 3-kinase (PI 3-kinase) comprising the catalytic p110 subunit covalently attached at the N-terminus to the iSH2 region of the regulatory subunit, p85. The invention discloses one form of the constitutively active kinase, p110*, which functions independently of growth factor stimulation. Expression vectors encoding a constitutively active PI 3-kinase and cells containing such expression vectors are provided. The invention also provides methods of using the constitutively active phosphatidylinositol 3-kinase to generate phosphoinositides, to identify cellular target proteins and associating molecules of PI 3-kinase, to screen for inhibitors of PI 3-kinase activity and to treat certain diseases, in particular, proliferative diseases. Kits comprising the constitutively active kinase are also provided.

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San Francisco, CA, United States of America

Anke Klippel