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Volume 272, Number 2, Issue of January 10, 1997 pp. 773-781
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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The Heterotrimeric G Protein G_i2 Mediates Lysophosphatidic Acid-stimulated Induction of the c-fos Gene in Mouse Fibroblasts

(Received for publication, July 31, 1996, and in revised form, October 15, 1996)

J. Kurt Chuprun , John R. Raymond ^¶ and Perry J. Blackshear

From the  Howard Hughes Medical Institute, Durham, North Carolina, the Departments of  Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, and the ^¶ Veterans Affairs Medical Center, Durham, North Carolina 27705

Lysophosphatidic acid (LPA) utilizes a heterotrimeric guanine nucleotide regulatory (G) protein-coupled receptor to activate the mitogen-activated protein kinase pathway and induce mitogenesis in fibroblasts and other cells. A single cell assay system was used to examine the functional interaction of the LPA receptor with G proteins in intact mouse fibroblasts, by measuring LPA-stimulated induction of the immediate-early gene, c-fos, as read out by a stably expressed fos-lacZ reporter gene. Pretreatment of these cells with pertussis toxin at 100 ng/ml almost completely abolished LPA-stimulated c-fos induction. Western blotting revealed that two pertussis toxin (PTX)-sensitive G proteins, G_i2 and G_i3, were present in membranes prepared from these cells, and Northern blotting confirmed the absence of message for other PTX-sensitive subunits. Microinjection of an _i1/_i2-specific antibody into living cells decreased LPA-stimulated induction of c-fos by 60%, whereas introduction of antibodies to either _i3 or ₁₆, a subtype not present in these cells but used as a control, decreased LPA-stimulated c-fos induction by only 19%. In contrast, the _i1/_i2-specific antibody had no effect on insulin-induced c-fos expression, which is thought to utilize a G protein-independent mechanism of signaling. In addition, cellular expression of an epitope-tagged PTX-resistant mutant of G_i2, but not PTX-resistant G_i3, restored LPA-stimulated c-fos induction in cells in which endogenous G protein  subunits were uncoupled from the receptor by pretreatment with PTX. Together, these results provide conclusive in vivo evidence that G_i2 is the PTX-sensitive G protein  subunit which mediates LPA-stimulated c-fos induction and perhaps mitogenesis in these cells.

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