TY - JOUR
T1 - Vav1
T2 - An oncogene that regulates specific transcriptional activation of T cells
AU - Katzav, Shulamit
PY - 2004/4/1
Y1 - 2004/4/1
N2 - The nuclear factor of activated T cells (NFAT) proteins are a family of transcription factors whose activation is controlled by calcineurin, Ca 2+-dependent phosphatase. Once dephosphorylated, these proteins move to the nucleus where they interact with cofactors to form transcription factor complexes. Inhibition of NFAT proteins by immunosuppressants, such as cyclosporin A (CsA) and FK506, is used clinically to prevent transplant rejection. Although these drugs have revolutionized organ transplantation, their use is associated with severe side effects in other organs in which NFAT proteins are important. One of the signal transducers that controls NFAT activity is Vav1, which is exclusively expressed in the hematopoietic system. Vav1 contains numerous modular domains that enable its function as a guanine exchange factor (GEF) toward RhoGTPases as well as participate in protein-protein interactions. This review focuses on the mechanisms by which Vav1 regulates NFAT through GEF-dependent and -independent cascades, emphasizing the newly assigned role of Vav1 in the regulation of Ca 2+ release. Because of its restriction to hematopoietic cell lineages and its importance in the regulation of NFAT, targeting Vav1 and, in particular, its association with other proteins may offer a highly selective means of modifying T-cell behavior, thus allowing the development of more specific immunosuppressive therapies.
AB - The nuclear factor of activated T cells (NFAT) proteins are a family of transcription factors whose activation is controlled by calcineurin, Ca 2+-dependent phosphatase. Once dephosphorylated, these proteins move to the nucleus where they interact with cofactors to form transcription factor complexes. Inhibition of NFAT proteins by immunosuppressants, such as cyclosporin A (CsA) and FK506, is used clinically to prevent transplant rejection. Although these drugs have revolutionized organ transplantation, their use is associated with severe side effects in other organs in which NFAT proteins are important. One of the signal transducers that controls NFAT activity is Vav1, which is exclusively expressed in the hematopoietic system. Vav1 contains numerous modular domains that enable its function as a guanine exchange factor (GEF) toward RhoGTPases as well as participate in protein-protein interactions. This review focuses on the mechanisms by which Vav1 regulates NFAT through GEF-dependent and -independent cascades, emphasizing the newly assigned role of Vav1 in the regulation of Ca 2+ release. Because of its restriction to hematopoietic cell lineages and its importance in the regulation of NFAT, targeting Vav1 and, in particular, its association with other proteins may offer a highly selective means of modifying T-cell behavior, thus allowing the development of more specific immunosuppressive therapies.
UR - http://www.scopus.com/inward/record.url?scp=1642268790&partnerID=8YFLogxK
U2 - 10.1182/blood-2003-08-2834
DO - 10.1182/blood-2003-08-2834
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C2 - 14592821
AN - SCOPUS:1642268790
SN - 0006-4971
VL - 103
SP - 2443
EP - 2451
JO - Blood
JF - Blood
IS - 7
ER -