SPAK kinase is a substrate and target of PKCtheta in T-cell receptor-induced AP-1 activation pathway.
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Li Y, Hu J, Vita R, Sun B, Tabata H, Altman A
SPAK kinase is a substrate and target of PKCtheta in T-cell receptor-induced AP-1 activation pathway.
EMBO J. 2004 Mar 10;23(5):1112-22. Epub 2004 Feb 26.
- PubMed ID
- 14988727 [ View in PubMed]
- Abstract
Protein kinase C-theta (PKCtheta) plays an important role in T-cell activation via stimulation of AP-1 and NF-kappaB. Here we report the isolation of SPAK, a Ste20-related upstream mitogen-activated protein kinase (MAPK), as a PKCtheta-interacting kinase. SPAK interacted with PKCtheta (but not with PKCalpha) via its 99 COOH-terminal residues. TCR/CD28 costimulation enhanced this association and stimulated the catalytic activity of SPAK. Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. The magnitude and duration of TCR/CD28-induced endogenous SPAK activation were markedly impaired in PKCtheta-deficient T cells. Transfected SPAK synergized with constitutively active PKCtheta to activate AP-1, but not NF-kappaB. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK. Conversely, a SPAK-specific RNAi or a dominant-negative SPAK mutant inhibited PKCtheta- and TCR/CD28-induced AP-1, but not NF-kappaB, activation. These results define SPAK as a substrate and target of PKCtheta in a TCR/CD28-induced signaling pathway leading selectively to AP-1 (but not NF-kappaB) activation.