Positive feedback regulation of PLC gamma 1/Ca2+ signaling by PKC theta in restimulated T cells via a Tec kinase-dependent pathway

• Published in: European journal of immunology 2004-07, Vol.34 (7), p.2001-2011
• Main Authors: Altman, A., Kaminski, S., Busuttil, V., Droin, N., Hu, J. R., Tadevosyan, Y., Hipskind, R. A., Villalba, Martin
• Format: Article
• Language: English
• Subjects: Biochemistry, Molecular Biology; Life Sciences
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200324625

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.