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

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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 $beta$ (p85 $alpha$ -p110 $beta$ ) 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-K $alpha$ ) (p85 $alpha$ -p110 $alpha$ ) is required for DNA synthesis inducedby 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 PI3-K $beta$ (p85 $alpha$ -p110 $beta$ ) during mitogenesis. By using antibodies specificto p110 $beta$ we showed that PI 3-K $beta$ is expressed in NIH 3T3 cells.PI 3-K $beta$ and PI 3-K $alpha$ have common features: PI 3-K $beta$ is tightly associatedwith a protein serine kinase that phosphorylates p85 $alpha$ , it interactswith the Src-middle T antigen complex and the activated platelet-derivedgrowth factor (PDGF) receptor in fibroblasts in vivo, and it becomestyrosine phosphorylated after PDGF stimulation. PI 3-K $beta$ was alsoactivated in Swiss 3T3 and Cos7 cells stimulated with lysophosphatidicacid (LPA), a mitogen that interacts with a heterotrimeric G protein-coupledreceptor. In contrast PI 3-K $alpha$ was activated to a lesser extentin these cells. Microinjection of neutralizing antibodies specificfor p110 $beta$ into quiescent fibroblasts inhibited DNA synthesis inducedby both insulin and LPA but poorly affected PDGF receptor signaling.Therefore, PI 3-K $beta$ plays an important role in transmitting themitogenic response induced by some, but not all, growth factors.Finally, we show that while oncogenic V12Ras interacts with typeI PI 3-Ks, it could induce DNA synthesis in the absence of activePI 3-K $alpha$ and PI 3-K $beta$ , suggesting that Ras uses other effectorsfor DNAsynthesis.

^* 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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A Function for Phosphatidylinositol 3-Kinase (p85-p110) in Fibroblasts during Mitogenesis: Requirement for Insulin- and Lysophosphatidic Acid-Mediated Signal Transduction

A Function for Phosphatidylinositol 3-Kinase $beta$ (p85 $alpha$ -p110 $beta$ ) in Fibroblasts during Mitogenesis: Requirement for Insulin- and Lysophosphatidic Acid-Mediated Signal Transduction