Defects in actin-cap formation in Vav-deficient mice implicate an actin requirement for lymphocyte signal transduction

Abstract

These results indicate that Vav is required for cap formation in lymphocytes. Furthermore, the correlation between cap formation, IL-2 production and proliferation supports the hypothesis that an actin-dependent pathway is a source of specialized growth regulatory signals.

Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription

“…This very N-terminal stretch of 161 amino acids seems to comprise an important function for the transmission of signals which activate certain transcription factors and the MAPkinase p38. Our results of an important role for Vav1 in the activation of JNK do not contradict the data obtained from thymocytes derived from Vav1 knockout mice, which were shown to retain their inducible JNK activation Holsinger et al, 1998). Of note, these ®ndings were obtained by a loss-of-function approach and are therefore not inconsistent with our results of a Vav1-mediated JNK activation, which were measured by a gain-of-function approach.…”

“…Since Vav1 is located at an early point for many Ca 2+ -dependent and -independent signaling cascades, its targeted inactivation during apoptosis prevents the activation of the MAPK p38 as well as the induction of various transcription factors. Since the targeted deletion of Vav1 in mice leads to similar e ects than the actin polymerization inhibitor cytochalasin D Holsinger et al, 1998), the elimination of Vav1 probably also disables the cytoskeleton, which is a frequent caspase target. Taken together, the inactivation of Vav1 by caspases leads to pleiotropic e ects: loss of signal transmission for several signaling cascades and transcription factors and the prevention of IL-2 transcription.…”

“…Targeted gene disruption revealed the importance of Vav1 for receptor-mediated proliferation and TCR-mediated positive selection (Fischer et al, 1995;Tarakhovsky et al, 1995;Zhang et al, 1995;Turner et al, 1997). Vav1 is furthermore important for the reorganization of the cytoskeleton and actin polymerization which contributes to the clustering of TCRs into patches and caps Holsinger et al, 1998). Overexpression of Vav1 stimulates IL-2 expression by activating transcription factors such as NF-kB and by triggering the activity of mitogen-activated protein kinases (MAPKs) (Costello et al, 1999).…”

Vav1 transduces TCR signals required for LFA‐1 function and cell polarization at the immunological synapse

“…Furthermore Vav1-deficient T cells are defective in TCR-induced proliferation and cytokine synthesis [8][9][10][11]. Analysis of biochemical signaling pathways has shown that in the absence of Vav1, TCR-induced calcium flux, as well as ERK, NF-‹ B and phosphoinositide 3-OH kinase activation are reduced [10][11][12][13][14]. Vav1 is a guanine nucleotide exchange factor for members of the Rho-family of GTPases, in particular Rac1, Rac2, RhoG and possibly Cdc42, and its activity is regulated by tyrosine phosphorylation [5].…”

“…In view of the well established role for Rhofamily proteins in the regulation of the actin cytoskeleton, it has been proposed that Vav1 may transduce TCR signals to the rearrangement of the actin cytoskeleton. Indeed Vav1-deficient T cells were shown to be defective in TCR-induced actin polymerization [10,13].…”