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  • The EMBO Journal (1998) 17, 414 - 422
  • doi:10.1093/emboj/17.2.414

Activation of phospholipase Cbig gamma by PI 3-kinase-induced PH domain-mediated membrane targeting

M. Falasca2, S.K. Logan1, V.P. Lehto3, G. Baccante4, M.A. Lemmon5 and J. Schlessinger1

  1. Department of Pharmacology, NYU Medical Center, 550 First Avenue, New York, NY 10016, USA
  2. Department of Cell Biology and Oncology, Istituto di Ricerche Farmacologiche 'Mario Negri', Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, CH, Italy
  3. University of Oulu, Kajaanintie 52 D, SF-90220, Oulu, Finland
  4. Institute of Pathophysiology, School of Medicine, G.D'Annunzio University, 66013 Chieti, Italy
  5. Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6089, USA

Received 23 September 1997; Accepted 11 November 1997; Revised 11 November 1997

Signaling via growth factor receptors frequently results in the concomitant activation of phospholipase Cgamma (PLCgamma) and phosphatidylinositol (PI) 3-kinase. While it is well established that tyrosine phosphorylation of PLCgamma is necessary for its activation, we show here that PLCgamma is regulated additionally by the lipid products of PI 3-kinase. We demonstrate that the pleckstrin homology (PH) domain of PLCgamma binds to phosphatidylinositol 3,4,5-trisphosphate [PdtIns(3,4,5)P3], and is targeted to the membrane in response to growth factor stimulation, while a mutated version of this PH domain that does not bind PdtIns(3,4,5)P3 is not membrane targeted. Consistent with these observations, activation of PI 3-kinase causes PLCgamma PH domain-mediated membrane targeting and PLCgamma activation. By contrast, either the inhibition of PI 3-kinase by overexpression of a dominant-negative mutant or the prevention of PLCgamma membrane targeting by overexpression of the PLCgamma PH domain prevents growth factor-induced PLCgamma activation. These experiments reveal a novel mechanism for cross-talk and mutual regulation of activity between two enzymes that participate in the control of phosphoinositide metabolism.

  • Keywords:

    • PH domains,
    • phosphoinositides,
    • phospholipase Cgamma1,
    • PI 3-kinase