RasGRP1 regulates antigen-induced developmental programming by naive CD8 T cells.

Ag encounter by naive CD8 T cells initiates a developmental program consisting of cellular proliferation, changes in gene expression, and the formation of effector and memory T cells. The strength and duration of TCR signaling are known to be important parameters regulating the differentiation of naive CD8 T cells, although the molecular signals arbitrating these processes remain poorly defined. The Ras-guanyl nucleotide exchange factor RasGRP1 has been shown to transduce TCR-mediated signals critically required for the maturation of developing thymocytes.

Differential expression and activation of Rab27A in human eosinophils: relationship to blood eosinophilia.

Eosinophil degranulation is thought to play a pathophysiological role in asthma. Rab27A is a GTP-binding protein that is known to be essential for the degranulation of several leukocyte subsets and thus may be essential for eosinophil granule exocytosis. Here, we show that Rab27A mRNA and protein are expressed in human eosinophils.

Vesicle-associated membrane protein 7 (VAMP-7) is essential for target cell killing in a natural killer cell line.

Natural killer cells recognize and induce apoptosis in foreign, transformed or virus-infected cells through the release of perforin and granzymes from secretory lysosomes. Clinically, NK-cell mediated killing is a major limitation to successful allo- and xenotransplantation. The molecular mechanisms that regulate the fusion of granzyme B-containing secretory lysosomes to the plasma membrane in activated NK cells, prior to target cell killing, are not fully understood.

Differential secretion of cytokines.

Eosinophil granules store a vast array of cytokines and chemokines, many of which possess opposing activities. Specific stimuli can induce the release of entire granules or selective mediators through a process termed piecemeal degranulation. Until recently, the mechanisms that governed the decision to opt for either of these processes were unknown.

The role of RasGRPs in regulation of lymphocyte proliferation.

RasGRP1 links TCR signaling to Ras in T cells, while both RasGRP1 and RasGRP3 link BCR signaling to Ras in B cells. T cells deficient in RasGRP1 have defective proliferative responses as do B cells deficient in both RasGRP1 and RasGRP3, confirming the importance of Ras activation in lymphocyte proliferation. While aged Rasgrp1-/- mice develop late-onset autoimmunity characterized by splenomegaly and the presence of anti-nuclear antibodies (ANA), the additional loss of RasGRP3 expression inhibits this phenotype.

RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling.

The RasGRPs are a family of Ras activators that possess diacylglycerol-binding C1 domains. In T cells, RasGRP1 links TCR signaling to Ras. B cells coexpress RasGRP1 and RasGRP3.

Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells.

B-cell receptor (BCR) signaling activates a number of intracellular signaling molecules including phospholipase C-gamma2 (PLC-gamma2), which generates membrane diacylglycerol (DAG). DAG recruits both protein kinase C (PKC) and RasGRP family members to the membrane and contributes to their activation. We have hypothesized that membrane colocalization facilitates activation of RasGRP3 by PKC.

Effects of inhibition of myocardial extracellular-responsive kinase and P38 mitogen-activated protein kinase on mechanical function of rat hearts after prolonged hypothermic ischemia.

Background: Mitogen-activated protein kinases (MAPKs), including extracellular-responsive kinase (ERK) and p38 MAPK, are activated by stresses associated with hypothermia-rewarming and ischemia-reperfusion. Their activation in heart is associated with beneficial (preconditioning) and adverse effects (apoptosis and impaired contractility). This study determined whether ERK and p38 MAPK activities are altered by hypothermic ischemia and normothermic reperfusion and the consequences of their inhibition on recovery of myocardial function.