Just parking these two abstracts here so I can find them again, in the event that I need them. Also thought that others might be interested in Vav.....
J Immunol 1998 Nov 1;161(9):4506-12
Uncoupling activation-dependent HS1 phosphorylation from nuclear
factor of activated T cells transcriptional activation in Jurkat T cells:
differential signaling through CD3 and the costimulatory receptors CD2
and CD28.
Hutchcroft JE, Slavik JM, Lin H, Watanabe T, Bierer BE
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
CD3, CD2, and CD28 are functionally distinct receptors on T lymphocytes. Engagement of any of these receptors induces the
rapid tyrosine phosphorylation of a shared group of intracellular signaling proteins, including Vav, Cbl, p85 phosphoinositide
3-kinase, and the Src family kinases Lck and Fyn. Ligation of CD3 also induces the tyrosine phosphorylation of HS1, a
75-kDa hematopoietic cell-specific intracellular signaling protein of unknown function. We have examined changes in HS1
phosphorylation after differential stimulation of CD3, CD2, and CD28 to elucidate its role in T cells and to further delineate the
signaling pathways recruited by these receptors. Unlike ligation of CD3, stimulation with anti-CD28 mAb or CHO cells
expressing the CD28 ligands CD80 or CD86 did not lead to tyrosine phosphorylation of HS1 in Jurkat T cells. Additionally, no
tyrosine phosphorylation of HS1 was induced by mitogenic pairs of anti-CD2 mAbs capable of activating the transcription
factor NFAT (nuclear factor of activated T cells). Costimulation through CD28 and/or CD2 did not modulate the
CD3-dependent phosphorylation of HS1. In vivo studies indicated that CD3-induced HSI phosphorylation was dependent
upon both the Src family tyrosine kinase Lck and the tyrosine phosphatase CD45, did not require MEK1 kinase activity, and
was regulated by protein kinase C activation. Thus, although CD3, CD28, and CD2 activate many of the same signaling
molecules, they differed in their capacity to induce the tyrosine phosphorylation of HSI. Furthermore, activation-dependent
tyrosine phosphorylation of HS1 was not required for NFAT transcriptional activation.
J Exp Med 1998 Dec 7;188(11):2099-111
Vav regulates peptide-specific apoptosis in thymocytes.
Kong YY, Fischer KD, Bachmann MF, Mariathasan S, Kozieradzki I, Nghiem MP, Bouchard D, Bernstein A,
Ohashi PS, Penninger JM
Amgen Institute, University of Toronto, Toronto, Ontario, Canada M5G 2C1.
[Medline record in process]
The protooncogene Vav functions as a GDP/GTP exchange factor (GEF) for Rho-like small GTPases involved in cytoskeletal
reorganization and cytokine production in T cells. Gene-targeted mice lacking Vav have a severe defect in positive and negative
selection of T cell antigen receptor transgenic thymocytes in vivo, and vav-/- thymocytes are completely resistant to
peptide-specific and anti-CD3/anti-CD28-mediated apoptosis. Vav acts upstream of mitochondrial pore opening and caspase
activation. Biochemically, Vav regulates peptide-specific Ca2+ mobilization and actin polymerization. Peptide-specific cell
death was blocked both by cytochalasin D inhibition of actin polymerization and by inhibition of protein kinase C (PKC).
Activation of PKC with phorbol ester restored peptide-specific apoptosis in vav-/- thymocytes. Vav was found to bind
constitutively to PKC-theta in thymocytes. Our results indicate that peptide-triggered thymocyte apoptosis is mediated via Vav
activation, changes in the actin cytoskeleton, and subsequent activation of a PKC isoform. |
