PMID- 10636924
OWN - NLM
STAT- MEDLINE
DCOM- 20000224
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 275
IP  - 3
DP  - 2000 Jan 21
TI  - A guanine nucleotide exchange factor-independent function of Vav1 in
      transcriptional activation.
PG  - 2185-90
AB  - T cell antigen receptor (TCR) stimulation induces the tyrosine phosphorylation of
      several intracellular proteins including the protooncogene Vav1. Vav1 expression 
      is necessary for normal T cell development and activation. We previously showed
      that overexpression of Vav1 in Jurkat T cells potentiates the activity of the
      transcription factor nuclear factor of activated T cells (NF-AT). The mechanism
      by which Vav1 participates in TCR signaling events is not clear. Vav1 contains a 
      guanine nucleotide exchange factor (GEF) domain that has specificity for Rac and 
      other Rho GTPases that have been recently implicated in T cell activation events.
      Significantly, in vitro tyrosine phosphoryation of Vav1 by Lck activates its
      exchange activity. This Lck-mediated phosphorylation of Vav1 has been reported to
      depend upon Tyr-174 in Vav1, a site implicated in Vav1 function by other studies 
      as well. In this report, we demonstrated that Tyr-174 is not required for the
      TCR-induced phosphorylation of Vav1 in vivo. Moreover, mutation of Tyr-174
      augmented the ability of Vav1 to up-regulate NF-AT activation as well as the Vav1
      GEF function leading to Rac activation. However, we also showed that the GEF
      activity of Vav1 was neither sufficient nor necessary for potentiation of NF-AT, 
      and thereby we identify a GEF-independent role of Vav1 in potentiating
      NF-AT-driven transcription. Oncogenic Vav1 in which the amino-terminal 67 amino
      acids were deleted had elevated GEF activity but did not potentiate NF-AT when
      overexpressed in Jurkat cells. We also showed that a GEF mutant form of Vav1 that
      had impaired GEF function could still potentiate NF-AT. These studies reveal a
      previously unrecognized negative regulatory function of Tyr-174 in Vav1 and
      suggest that domains other than the Vav1 GEF domain contribute to TCR signals
      leading to NF-AT activation.
FAU - Kuhne, M R
AU  - Kuhne MR
AD  - Departments of Medicine and of Microbiology and Immunology, Howard Hughes Medical
      Institute, University of California at San Francisco, San Francisco, California
      94143, USA.
FAU - Ku, G
AU  - Ku G
FAU - Weiss, A
AU  - Weiss A
LA  - eng
GR  - CA72531/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Proto-Oncogene Proteins c-vav)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Transcription Factors)
RN  - 0 (VAV1 protein, human)
RN  - 42HK56048U (Tyrosine)
RN  - 47E5O17Y3R (Phenylalanine)
RN  - EC 3.6.5.2 (rac GTP-Binding Proteins)
SB  - IM
MH  - *Cell Cycle Proteins
MH  - DNA-Binding Proteins/metabolism
MH  - Enzyme Activation
MH  - Guanine Nucleotide Exchange Factors/*metabolism
MH  - Humans
MH  - Jurkat Cells
MH  - Mutagenesis
MH  - NFATC Transcription Factors
MH  - *Nuclear Proteins
MH  - Phenylalanine/metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins/genetics/*physiology
MH  - Proto-Oncogene Proteins c-vav
MH  - Receptors, Antigen, T-Cell/metabolism
MH  - Transcription Factors/metabolism
MH  - Transcription, Genetic/physiology
MH  - Transcriptional Activation/*physiology
MH  - Transfection
MH  - Tyrosine/metabolism
MH  - rac GTP-Binding Proteins/metabolism
EDAT- 2000/01/15 09:00
MHDA- 2000/02/26 09:00
CRDT- 2000/01/15 09:00
PHST- 2000/01/15 09:00 [pubmed]
PHST- 2000/02/26 09:00 [medline]
PHST- 2000/01/15 09:00 [entrez]
AID - 10.1074/jbc.275.3.2185 [doi]
AID - S0021-9258(18)31157-8 [pii]
PST - ppublish
SO  - J Biol Chem. 2000 Jan 21;275(3):2185-90. doi: 10.1074/jbc.275.3.2185.