4q9z

Structural highlights

Function

[KPCT_HUMAN] Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates to the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1.^{[1] [2] [3] [4] [5] [6] [7] [8]}

See Also

• Protein kinase C

References

1. ↑ Baier-Bitterlich G, Uberall F, Bauer B, Fresser F, Wachter H, Grunicke H, Utermann G, Altman A, Baier G. Protein kinase C-theta isoenzyme selective stimulation of the transcription factor complex AP-1 in T lymphocytes. Mol Cell Biol. 1996 Apr;16(4):1842-50. PMID:8657160
2. ↑ Villalba M, Bushway P, Altman A. Protein kinase C-theta mediates a selective T cell survival signal via phosphorylation of BAD. J Immunol. 2001 May 15;166(10):5955-63. PMID:11342610
3. ↑ 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. PMID:14988727 doi:http://dx.doi.org/10.1038/sj.emboj.7600125
4. ↑ Li Y, Soos TJ, Li X, Wu J, Degennaro M, Sun X, Littman DR, Birnbaum MJ, Polakiewicz RD. Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). J Biol Chem. 2004 Oct 29;279(44):45304-7. Epub 2004 Sep 10. PMID:15364919 doi:http://dx.doi.org/10.1074/jbc.C400186200
5. ↑ Thuille N, Heit I, Fresser F, Krumbock N, Bauer B, Leuthaeusser S, Dammeier S, Graham C, Copeland TD, Shaw S, Baier G. Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCtheta in T lymphocytes. EMBO J. 2005 Nov 16;24(22):3869-80. Epub 2005 Oct 27. PMID:16252004 doi:http://dx.doi.org/7600856
6. ↑ Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-Garcia ME, Ovechkina YL, Rawlings DJ. Phosphorylation of the CARMA1 linker controls NF-kappaB activation. Immunity. 2005 Dec;23(6):561-74. PMID:16356855 doi:http://dx.doi.org/10.1016/j.immuni.2005.09.014
7. ↑ Manicassamy S, Gupta S, Huang Z, Sun Z. Protein kinase C-theta-mediated signals enhance CD4+ T cell survival by up-regulating Bcl-xL. J Immunol. 2006 Jun 1;176(11):6709-16. PMID:16709830
8. ↑ Gruber T, Hermann-Kleiter N, Hinterleitner R, Fresser F, Schneider R, Gastl G, Penninger JM, Baier G. PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation. Sci Signal. 2009 Jun 23;2(76):ra30. doi: 10.1126/scisignal.2000046. PMID:19549985 doi:http://dx.doi.org/10.1126/scisignal.2000046
9. ↑ George DM, Breinlinger EC, Friedman M, Zhang Y, Wang J, Argiriadi M, Bansal-Pakala P, Barth M, Duignan DB, Honore P, Lang Q, Mittelstadt S, Potin D, Rundell L, Edmunds JJ. Discovery of Selective and Orally Bioavailable Protein Kinase Ctheta (PKCtheta) Inhibitors from a Fragment Hit. J Med Chem. 2014 Jul 7. PMID:25000588 doi:http://dx.doi.org/10.1021/jm500669m