An epidermal growth factor receptor/Gab1 signaling pathway is required for activation of phosphoinositide 3-kinase by lysophosphatidic acid.
Phosphoinositide 3-kinase (PI3K) has been shown to play an essential role in G protein-induced signaling even in non-myeloid cells where few agonists of G protein-coupled receptors are known to activate PI3K. We have identified adherent cell lines where lysophosphatidic acid (LPA) strongly and rapidly activates the accumulation of PI3K lipid products. The process is not modified by expression of a kinase-dead mutant of the Gbetagamma-responsive PI3K p110gamma. In contrast, it is inhibited by genistein or expression of a dominant negative mutant of p85 and potentiated by overexpressing wild-type p110alpha or -beta but not -gamma. By using a specific chemical inhibitor of the epidermal growth factor receptor (EGFR) and expression of a dominant negative mutant, we have observed that recruitment of p85/p110 PI3Ks occurs through transactivation of the EGFR by LPA and downstream mobilization of the docking protein Gab1 that associates with p85 upon LPA stimulation. Finally, we show that LPA cannot activate PI3K in cell lines lacking the EGFR/Gab1 pathway, including cells that transactivate the PDGF receptor. Altogether, these results demonstrate that activation of PI3K by LPA is conditioned by the ability of LPA to transactivate an EGFR/Gab1 signaling pathway.
Laffargue
M
M
INSERM U326, IFR 30, Hopital Purpan, 31059 Toulouse, France.
Raynal
P
P
Yart
A
A
Peres
C
C
Wetzker
R
R
Roche
S
S
Payrastre
B
B
Chap
H
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D008246:Lysophospholipids; D010716:Phosphatidylinositols; D010750:Phosphoproteins; D019000:Phosphotyrosine; D019833:Genistein; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D019204:GTP-Binding Proteins