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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3648-3654.
Prepublished online as a Blood First Edition Paper on January 18, 2005; DOI 10.1182/blood-2004-10-3916.


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IMMUNOBIOLOGY

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

Yong Zheng, Huaizhi Liu, Jason Coughlin, Jing Zheng, Liang Li, and James C. Stone

From the Departments of Biochemistry and Chemistry, University of Alberta, Edmonton, AB, Canada.

B-cell receptor (BCR) signaling activates a number of intracellular signaling molecules including phospholipase C–{gamma}2 (PLC-{gamma}2), 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. Here we demonstrate that PKC{theta} phosphorylates RasGRP3 on Thr133 in vitro, as determined by mass spectrometry. RasGRP3 with a Thr133Ala substitution is a poor PKC substrate in vitro and a poor Ras activator in vivo. Antiphosphopeptide antibodies recognize Thr133-phosphorylated RasGRP3 in B cells after BCR stimulation or DAG analog treatment, but much less so in resting cells. PKC inhibitors block RasGRP3 Thr133 phosphorylation and Ras–extracellular signal-related kinase (Erk) signaling with a similar pattern. After stimulation of T-cell receptor (TCR) or DAG analog treatment of T cells, PKC-catalyzed phosphorylation of RasGRP1 occurs on the homologous residue, Thr184. These studies shed light on the proposed "PKC-Ras pathway" and support the hypothesis that RasGRP phosphorylation by PKC is a mechanism that integrates DAG signaling systems in T and B cells. PKC-mediated regulation of RasGRPs in lymphocytes may generate cooperative signaling in response to increases in DAG. The mast- and myeloid-selective family member RasGRP4 is regulated by different means.


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