Abstract

The Ras and Rho proteins function as critical transducers in the T-cell antigen receptor (TCR)-linked signaling cascade. These GTPases are activated by a family of guanine nucleotide exchange factors (GEFs) that includes Vav, a member of the Dbl family of GEFs. Earlier studies have shown that Vav cooperates with the Ras signaling cascade in activated T cells, and that the function of endogenous Vav may be quite different from that observed when the protein is over-expressed in mammalian cells. The following specific aims will be pursued: (1) to analyze the GEF activity of Vav, and to determine the impact of protein tyrosine phosphorylation on this activity, (2) to study the function of Vav in signaling pathways leading to growth versus cytoskeletal reorganization in T cells, (3) to identify protein serine-threonine kinases located downstream of Vav, and (4) to analyze the ability of wild-type and mutated Vav to reconstitute T-cell development and TCR-mediated activation in Vav-deficient mice.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050819-08
Application #
6385869
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Marino, Pamela
Project Start
1994-05-01
Project End
2002-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
8
Fiscal Year
2001
Total Cost
$320,811
Indirect Cost

  Institution

Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Charvet, Celine; Canonigo, Ann Janette; Becart, Stephane et al. (2006) Vav1 promotes T cell cycle progression by linking TCR/CD28 costimulation to FOXO1 and p27kip1 expression. J Immunol 177:5024-31
Tanaka, Yoshihiko; So, Takanori; Lebedeva, Svetlana et al. (2005) Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice. Blood 106:1286-95
Charvet, Celine; Canonigo, Ann Janette; Billadeau, Daniel D et al. (2005) Membrane localization and function of Vav3 in T cells depend on its association with the adapter SLP-76. J Biol Chem 280:15289-99
Kaminski, S; Del Pozo, M A; Hipskind, R A et al. (2004) Distinct functions of Vav1 in JNK1 activation in Jurkat T cells versus non-haematopoietic cells. Scand J Immunol 59:527-35
del Pozo, Miguel Angel; Schwartz, Martin A; Hu, Junru et al. (2003) Guanine exchange-dependent and -independent effects of Vav1 on integrin-induced T cell spreading. J Immunol 170:41-7
Sedwick, Caitlin E; Altman, Amnon (2002) Ordered just so: lipid rafts and lymphocyte function. Sci STKE 2002:re2
Cao, Youjia; Janssen, Erin M; Duncan, Andrew W et al. (2002) Pleiotropic defects in TCR signaling in a Vav-1-null Jurkat T-cell line. EMBO J 21:4809-19
Villalba, Martin; Bi, Kun; Hu, Junru et al. (2002) Translocation of PKC[theta] in T cells is mediated by a nonconventional, PI3-K- and Vav-dependent pathway, but does not absolutely require phospholipase C. J Cell Biol 157:253-63
Isakov, Noah; Altman, Amnon (2002) Protein kinase C(theta) in T cell activation. Annu Rev Immunol 20:761-94
Villalba, Martin; Altman, Amnon (2002) Protein kinase C-theta (PKCtheta), a potential drug target for therapeutic intervention with human T cell leukemias. Curr Cancer Drug Targets 2:125-37

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