Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor.
BACKGROUND
Vav is a guanine-nucleotide exchange factor for the Rho-like small GTPases RhoA, Rac1 and Cdc42, which regulate cytoskeletal reorganization and activation of stress-activated protein kinases (SAPK/JNKs). Vav is expressed in hematopoietic cells and is phosphorylated in T and B cells following activation of various growth factor or antigen receptors. Vav interacts with several signaling molecules in T cells, but the functional relevance of these interactions is established only for Slp76: they cooperate to induce activity of the transcription factor NF-AT and interleukin-2 expression. We have investigated the role of Vav in T cells by generating vav-/- mice.


RESULTS
Mice deficient for vav were viable and healthy, but had impaired T-cell development. In vav-/- T cells, in response to activation of the T-cell receptor (TCR), cell cycle progression, induction of NF-ATc1 activity, downregulation of the cell-cycle inhibitor p27Kip1, interleukin-2 production, actin polymerization and the clustering of TCRs into patches and caps--a cytoskeletal reorganization process--were defective. TCR-mediated activation of mitogen-activated protein kinase and SAPK/JNK was unaffected. Ca2+ mobilization was impaired in vav-/- thymocytes and T cells. In wild-type cells, Vav constitutively associated with the cytoskeletal membrane anchors talin and vinculin. In the absence of Vav, phosphorylation of Slp76, Slp76-talin interactions, and recruitment of the actin cytoskeleton to the CD3 zeta chain of the TCR co-receptor were impaired.


CONCLUSIONS
Vav is a crucial regulator of TCR-mediated Ca2+ flux, cytoskeletal reorganization and TCR clustering, and these are required for T-cell maturation, interleukin-2 production and cell cycle progression.
Fischer
K D
KD
Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), University of Wuerzburg, Germany. imsd066@rzbox.uni-wuerzburg.de
Kong
Y Y
YY
Nishina
H
H
Tedford
K
K
Marengère
L E
LE
Kozieradzki
I
I
Sasaki
T
T
Starr
M
M
Chan
G
G
Gardener
S
S
Nghiem
M P
MP
Bouchard
D
D
Barbacid
M
M
Bernstein
A
A
Penninger
J M
JM
D000199:Actins / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D018797:Cell Cycle Proteins; D003599:Cytoskeleton / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000502:physiology
D000199:Actins; D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse