Abstract
Robust elevation of the cytosolic calcium concentration is a crucial early step for T cell activation triggered by the T cell antigen receptor. Vav1 is a proto-oncogene expressed in hematopoietic cells that is indispensable for transducing the calcium-mobilizing signal. Following T cell receptor stimulation, Vav1 facilitates formation of signaling microclusters through multiple interactions with other proteins participating in the signaling cascade. Truncation of the N terminus of Vav1 produces its oncogenic version, which is unable to support normal calcium flux following T cell activation. We show here that truncation of the N-terminal region of Vav1 alters the fine structure of protein complexes in the signaling clusters, affecting the interaction of Vav1 with phospholipase Cγ1 (PLCγ1). This alteration is accompanied by a decrease in PLCγ1 phosphorylation and inhibition of inositol 1,4,5-trisphosphate production. We suggest that the structural integrity of the N-terminal region of Vav1 is important for the proper formation of the Vav1-associated signaling complexes. The oncogenic truncation of this region elicits conformational changes that interfere with the Vav1-mediated activation of PLCγ1 and that inhibit calcium mobilization.
Highlights
The oncogenic version of Vav1 inhibits calcium signaling in T cells
Upon T cell antigen receptor (TCR) stimulation, Vav1 is recruited to the TCR-proximal protein complexes, where it serves as a scaffold for other signaling proteins within the complexes [23,24,25,26]
calponin homology (CH) domaintruncated oncoVav1 is recruited to the signaling clusters following TCR stimulation but fails to mediate Ca2ϩ mobilization
Summary
The oncogenic version of Vav inhibits calcium signaling in T cells. Results: Oncogenic Vav alters the fine structure of the signaling clusters and inhibits phospholipase C␥1 (PLC␥1). We show here that truncation of the N-terminal region of Vav alters the fine structure of protein complexes in the signaling clusters, affecting the interaction of Vav with phospholipase C␥1 (PLC␥1). This alteration is accompanied by a decrease in PLC␥1 phosphorylation and inhibition of inositol 1,4,5-trisphosphate production. We show here that truncation of the CH domain alters the fine structure of protein complexes in the signaling clusters; the interaction of Vav with PLC␥1 is affected This alteration is accompanied by a decrease in PLC␥1 phosphorylation and inhibition of IP3 production. The oncogenic truncation of this region elicits conformational changes that interfere with the Vav1-mediated activation of PLC␥1 and that inhibit TCR-induced calcium mobilization
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