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Volume 271, Number 43, Issue of October 25, 1996 pp. 26962-26970
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Association of a p95 Vav-containing Signaling Complex with the FcRI  Chain in the RBL-2H3 Mast Cell Line
EVIDENCE FOR A CONSTITUTIVE IN VIVO ASSOCIATION OF Vav WITH Grb2, Raf-1, AND ERK2 IN AN ACTIVE COMPLEX

(Received for publication, June 17, 1996)

James S. Song , Jorge Gomez , Louis F. Stancato and Juan Rivera

From the Section on Chemical Immunology, NIAMSD, and the  Laboratory of Cellular and Molecular Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892

Aggregation of the high affinity receptor for IgE (FcRI) on the mucosal mast cell line, RBL-2H3, results in the rapid and persistent tyrosine phosphorylation of Vav. Immunoprecipitation of Vav from activated cells revealed co-immunoprecipitated phosphoproteins of molecular weights identical to the FcRI  and  chains, and the former was reactive with antibody to the FcRI  chain. Conversely, Western blots revealed the presence of p95 Vav in FcRI immunoprecipitates. The association of Vav and of Grb2 with the receptor was found to be regulated by aggregation of the receptor, and the interaction of Vav with the FcRI was localized to the  chain. To gain insight on the signaling pathway in which Vav participates, we investigated the in vivo associations of Vav with other molecules. A reducible chemical cross-linking agent was used to covalently maintain protein interactions under nonreducing conditions. A fraction of Vav increased in mass to form a complex of >300 kDa in molecular mass. Under reducing conditions the cross-linked Vav immunoprecipitates showed the presence of Grb2, Raf-1, and p42^mapk (ERK2). In vitro kinase assays of Raf-1 activity associated with Vav revealed that this complex had an activity greater than that of Raf-1 derived from nonactivated cells, and aggregation of the FcRI did not modulate this activity. In contrast, aggregation of the FcRI increased the total Raf-1 activity by 2-5-fold. These results demonstrate that Vav associates constitutively with components of the mitogen-activated protein kinase pathway to form an active multimeric signaling complex whose in vivo activity and associations may be directed by aggregation of the FcRI. The findings of this study may also be relevant to other members of the immune recognition receptor family that share the T-cell antigen receptor / chains.

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