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Molecular and Cellular Biology, December 1998, p. 7119-7129, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Function for Phosphatidylinositol 3-Kinase beta  (p85alpha -p110beta ) in Fibroblasts during Mitogenesis: Requirement for Insulin- and Lysophosphatidic Acid-Mediated Signal Transduction

Serge Roche,1,2,* J. Downward,3 Patrick Raynal,4 and Sara A. Courtneidge5

CNRS EP612 Faculté de Pharmacie, 34060 Montpellier,1 CRBM, CNRS UPR1086, 34293 Montpellier Cedex 5,2 and INSERM U326 Hôpital Purpan, 31059 Toulouse,4 France; Imperial Cancer Research Fund, London W2CA 3PX, United Kingdom3; and SUGEN Inc., Redwood City, California 940635

Received 2 April 1998/Returned for modification 11 May 1998/Accepted 7 September 1998

We have previously shown that phosphatidylinositol 3-kinase alpha  (PI 3-Kalpha ) (p85alpha -p110alpha ) is required for DNA synthesis induced by various growth factors (S. Roche, M. Koegl, and S. A. Courtneidge, Proc. Natl. Acad. Sci. USA 91:9185-9189, 1994) in fibroblasts. In the present study, we have investigated the function of PI 3-Kbeta (p85alpha -p110beta ) during mitogenesis. By using antibodies specific to p110beta we showed that PI 3-Kbeta is expressed in NIH 3T3 cells. PI 3-Kbeta and PI 3-Kalpha have common features: PI 3-Kbeta is tightly associated with a protein serine kinase that phosphorylates p85alpha , it interacts with the Src-middle T antigen complex and the activated platelet-derived growth factor (PDGF) receptor in fibroblasts in vivo, and it becomes tyrosine phosphorylated after PDGF stimulation. PI 3-Kbeta was also activated in Swiss 3T3 and Cos7 cells stimulated with lysophosphatidic acid (LPA), a mitogen that interacts with a heterotrimeric G protein-coupled receptor. In contrast PI 3-Kalpha was activated to a lesser extent in these cells. Microinjection of neutralizing antibodies specific for p110beta into quiescent fibroblasts inhibited DNA synthesis induced by both insulin and LPA but poorly affected PDGF receptor signaling. Therefore, PI 3-Kbeta plays an important role in transmitting the mitogenic response induced by some, but not all, growth factors. Finally, we show that while oncogenic V12Ras interacts with type I PI 3-Ks, it could induce DNA synthesis in the absence of active PI 3-Kalpha and PI 3-Kbeta , suggesting that Ras uses other effectors for DNA synthesis.

* Corresponding author. Present address: C.R.B.M., CNRS UPR1086, 1919 route de Mende, 34293 Montpellier, Cedex 5, France. Phone: 33 4 67 61 33 73. Fax: 33 4 67 52 15 59. E-mail: serger{at}crbm.cnrs-mop.fr.

Molecular and Cellular Biology, December 1998, p. 7119-7129, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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