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 PCK-Theta Pathway

Novel protein kinase C (nPKC), PKCtheta (PKCθ), is a calcium-independent, diacylglycerol (DAG)-dependent serine/threonine protein kinase, closely related to PKCdelta, that is expressed in testicular interstitial cells, capillary endothelial cells, skeletal muscle cells, neural cells and various hematopoietic cells, including megakaryocyte and erythroblast progenitor lines, platelets, mast cells, thymocytes, T-lymphomas, and mature T-cells.

PKCtheta has been linked to angiogenesis and wound repair response in capillary endothelial cells; to insulin signaling modulation in skeletal muscle cells, to differentiation in neural cells; to T-cell activation and survival responses in adult-T cells and to T-cell FasL ligand-mediated apoptosis in thymocytes. The most thoroughly studied PKCtheta role is in T-cell activation by TCR.CD3 complex CD28 costimulation by antigen presenting cells (APC). During antigen induced T-cell activation, PKCtheta translocates from the cytoplasm to lipid rafts and then to the central supramolecular activation cluster (c-SMAC) of the immunologic synapse.

T-cell activation by antigen-presenting cells (APC) initiates a series of coordinated signals that ensure cell survival, and induce cell proliferation and the production of IL-2 (or IL-4). This requires the activation of transcription factors including CREB, NFkappaB, AP-1 and NF-AT (NFAT). Activation of these gene regulators requires the integration of signals from the TCR.CD3 complex and the costimulator, CD28. PKCtheta plays a central role in the integration of these signals. PKCtheta supports the activation of CREB and in synergy with calcium activated calcineurin stimulates the activation of AP-1 and NFAT, through the MAP-kinase, JNK. PKCtheta also stimulates the translocation of NFkappaB from the cytoplasm to the nucleus through activation of the I-kappa kinase (IKK) complex beta subunit. PKCtheta promotes cell survival by several processes including the activation of CREB, induction of NFkappaB translocation to the nucleus and phosphorylation of the Bcl-2 family member, BAD.