The Rac1 guanine nucleotide exchange factor, Vav, is activated in hematopoietic cells in response to a large variety of stimuli. The downstream signaling events derived from Vav have been primarily characterized as leading to transcription or transformation. However, we report here that Vav and Rac1 in natural killer (NK) cells regulate the development of cell-mediated killing. There is a rapid increase in Vav tyrosine phosphorylation during the development of antibody-dependent cellular cytotoxicity and natural killing. In addition, overexpression of Vav, but not of a mutant lacking exchange factor activity, enhances both forms of killing by NK cells. Furthermore, dominant-negative Rac1 inhibits the development of NK cell–mediated cytotoxicity by two mechanisms: (a) conjugate formation between NK cells and target cells is decreased; and (b) those NK cells that do form conjugates have decreased ability to polarize their granules toward the target cell. Therefore, our results suggest that in addition to participating in the regulation of transcription, Vav and Rac1 are pivotal regulators of adhesion, granule exocytosis, and cellular cytotoxicity.
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3 August 1998
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August 03 1998
The Vav–Rac1 Pathway in Cytotoxic Lymphocytes Regulates the Generation of Cell-mediated Killing
Daniel D. Billadeau,
Daniel D. Billadeau
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
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Kathryn M. Brumbaugh,
Kathryn M. Brumbaugh
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
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Christopher J. Dick,
Christopher J. Dick
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
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Renee A. Schoon,
Renee A. Schoon
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
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Xose R. Bustelo,
Xose R. Bustelo
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
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Paul J. Leibson
Paul J. Leibson
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
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Daniel D. Billadeau
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
Kathryn M. Brumbaugh
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
Christopher J. Dick
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
Renee A. Schoon
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
Xose R. Bustelo
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
Paul J. Leibson
From the *Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and the ‡Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025
Address correspondence to Paul J. Leibson, Department of Immunology, Mayo Clinic, 200 First St., Rochester MN 55905. Phone: 507-284-4563; Fax: 507-284-1637; E-mail: [email protected]
This research was supported by the Mayo Foundation and by National Institutes of Health grant CA-47752. D.D. Billadeau is supported by National Institutes of Health Postdoctoral Training Grant CA-09441, and X.R. Bustelo is a Sinsheimer Scholar whose work is supported by grant CA-7373501.
Received:
March 24 1998
Revision Received:
May 19 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (3): 549–559.
Article history
Received:
March 24 1998
Revision Received:
May 19 1998
Citation
Daniel D. Billadeau, Kathryn M. Brumbaugh, Christopher J. Dick, Renee A. Schoon, Xose R. Bustelo, Paul J. Leibson; The Vav–Rac1 Pathway in Cytotoxic Lymphocytes Regulates the Generation of Cell-mediated Killing . J Exp Med 3 August 1998; 188 (3): 549–559. doi: https://doi.org/10.1084/jem.188.3.549
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