PKCtheta plays an essential role in activation of mature T cells. Here, we report that the TCR/CD28-induced tyrosine phosphorylation and activation of PLCgamma1 was significantly impaired in PKCtheta(-/-) primary, restimulated T cells. Consistent with this finding, receptor-induced Ca2+ mobilization, NF-AT DNA-binding activity and the membrane translocation of PKCalpha, a PLCgamma1-dependent conventional PKC, were also markedly reduced in the same cells. Moreover, a dominant-negative PLCgamma1 mutant blocked the PKCtheta-induced activation of an AP-1 reporter gene in Jurkat and primary cells. Regulation of PLCgamma1 signaling by PKCtheta required the tyrosine kinase Tec since a dominant-negative Tec mutant blocked PKCtheta-induced AP-1 (but not NF-kappaB) activation. In addition, wild-type Tec, but not Itk or Rlk, potently activated AP-1. Furthermore, Tec was found to constitutively associate with PKCtheta, an interaction that like AP-1 activation required the pleckstrin-homology domain of Tec. These findings define a novel PKCtheta-initiated pathway that regulates Ca2+ signaling and AP-1 activation via Tec and PLCgamma1. Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells.
Positive feedback regulation of PLC gamma 1/Ca2+ signaling by PKC theta in restimulated T cells via a Tec kinase-dependent pathway
Altman, A.; Kaminski, S.; Busuttil, V.; Droin, N.; Hu, J. R.; Tadevosyan, Y.; Hipskind, R. A.; Villalba, M.
European Journal of Immunology
2004-07 / vol 34 / pages 2001-2011
differentiation; antigen receptor; ap-1; c-theta; costimulation; family; kappa-b activation; nf-at; phospholipase c-gamma-1; pkc theta; plc gamma 1; pleckstrin homology domain; tec; translocation; tyrosine kinase