Abstract
Engagement of the T cell receptor (TCR).CD3 complex results in the induction of multiple intracellular events, with protein tyrosine kinases playing a pivotal role in their initiation. Biochemical studies also exist suggesting the involvement of heterotrimeric GTP-binding proteins (G proteins); however, the functional consequence of this participation in TCR.CD3-mediated signaling is unresolved. Here, we report TCR.CD3-mediated guanine nucleotide exchange among the 42-kDa G protein alpha subunits of the G alpha q/11 family, their physical association with CD3 epsilon, and the G alpha 11-dependent activation of phospholipase C beta. Protein tyrosine kinase inhibitors, however, abrogate TCR.CD3-mediated G protein activation. Quite interesting is the observation that cells transfected with a function-deficient mutant of G alpha 11 display diminished tyrosine phosphorylation of TCR.CD3 zeta and epsilon chains, as well as ZAP-70, upon anti-CD3 antibody triggering. These data indicate the involvement of the G alpha q/11 family in TCR.CD3 signaling at a step proximal to the receptor and suggest a reciprocal regulation between tyrosine kinases and G proteins in T cells.
Highlights
T lymphocytes acquire antigenic peptide/MHC recognition via their multicomponent T cell receptor (TCR)1 complex consisting of a polymorphic ␣ heterodimer and associated ␥, ␦, and ⑀ chains, termed CD3 [1]
Of the phospholipase C (PLC) isoforms expressed in T cells, only ␥1 has been shown to require tyrosine phosphorylation for its activation [5], while the  isoforms are activated as a result of interaction with the GTP-bound ␣ subunit of the heterotrimeric class of G proteins belonging to the Gq family [6, 7]
Activation of G Proteins upon TCR1⁄7CD3 Perturbation—Ligand occupancy of G protein-coupled receptors initiates the exchange of bound GDP for GTP, activating the ␣ subunit of the responding G protein and dissociating the trimer [22]
Summary
T lymphocytes acquire antigenic peptide/MHC recognition via their multicomponent T cell receptor (TCR) complex consisting of a polymorphic ␣ heterodimer and associated ␥, ␦, and ⑀ chains, termed CD3 [1]. The initial early events observed include tyrosine phosphorylation of a number of cellular substrates, and phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol bisphosphate [4]. The latter yields inositol 1,4,5-trisphosphate (IP3) and diacylglycerol, second messengers responsible for mobilization of intracellular calcium and activation of protein kinase C, respectively [4]. A number of biochemical events triggered by TCR1⁄7CD3-induced activation are ablated by agents that modulate the action of G proteins Pertinent to this is the ability of cholera toxin to inhibit the cellular proliferation and intracellular Ca2ϩ mobilization that is mediated by anti-CD3 antibody treatment of T cells [12, 13]. Our results reveal 1) TCR1⁄7CD3-mediated GTP exchange within G␣q/11, 2) physical association between G␣q/11 and CD3, 3) tyrosine kinase dependent-TCR1⁄7CD3-mediated G protein activation, 4) TCR1⁄7CD3-mediated PLC  activation and 5) G␣11 modulation of the tyrosine phosphorylation of the CD3 ⑀ and chains
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