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Molecular and Cellular Biology, September 2000, p. 6364-6373, Vol. 20, No. 17
Departments of Cell
Biology1 and
Genetics,3 The Center for Blood
Research,2 Department of Pediatrics
of The Children's Hospital,4 and Howard
Hughes Medical Institute,5 Harvard Medical
School, Boston, Massachusetts 02115
Received 15 February 2000/Returned for modification 23 March
2000/Accepted 8 June 2000
Vav proteins are guanine nucleotide exchange factors for Rho family
GTPases which activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. Vav proteins contain several protein binding domains which can link cell surface
receptors to downstream signaling proteins. Vav1 is expressed
exclusively in hematopoietic cells and tyrosine phosphorylated in
response to activation of multiple cell surface receptors. However, it is not known whether the recently identified isoforms Vav2 and Vav3,
which are broadly expressed, can couple with similar classes of
receptors, nor is it known whether all Vav isoforms possess identical functional activities. We expressed Vav1, Vav2, and Vav3
at equivalent levels to directly compare the responses of the Vav proteins to receptor activation. Although each Vav isoform was
tyrosine phosphorylated upon activation of representative receptor tyrosine kinases, integrin, and lymphocyte antigen receptors, we found unique aspects of Vav protein coupling in each receptor pathway. Each Vav protein coprecipitated with activated epidermal growth factor and platelet-derived growth factor (PDGF) receptors, and
multiple phosphorylated tyrosine residues on the PDGF receptor were
able to mediate Vav2 tyrosine phosphorylation. Integrin-induced tyrosine phosphorylation of Vav proteins was not detected in
nonhematopoietic cells unless the protein tyrosine kinase Syk was also
expressed, suggesting that integrin activation of Vav proteins may be
restricted to cell types that express particular tyrosine kinases. In
addition, we found that Vav1, but not Vav2 or Vav3, can efficiently
cooperate with T-cell receptor signaling to enhance NFAT-dependent
transcription, while Vav1 and Vav3, but not Vav2, can enhance
NF
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Vav Family Proteins Couple to Diverse Cell
Surface Receptors


B-dependent transcription. Thus, although each Vav isoform can
respond to similar cell surface receptors, there are isoform-specific
differences in their activation of downstream signaling pathways.
*
Corresponding author. Mailing address: Department of
Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA
02115. Phone: (617) 432-3974. Fax: (617) 432-3969. E-mail:
Joan_Brugge{at}hms.harvard.edu.
Present address: Proteome, Inc., Beverly, MA 01915.
Present address: Division of Neurological Science, Hokkaido
University School of Medicine, Sapporo 060-8638, Japan.
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