ERK activation is only one role of PKC in TCR-independent cytotoxic T cell granule exocytosis

Abstract

Cytotoxic T cells (CTLs) kill target cells by releasing lytic agents via regulated exocytosis. Three signals are known to be required for exocytosis: an increase in intracellular Ca 2+ , activation of protein kinase C (PKC) and activation of extracellular signal regulated signal kinase (ERK). ERK activation required for exocytosis depends on activity of PKC. The simplest possibility is that the sole effect of PKC required for exocytosis is ERK activation. Testing this requires dissociating ERK and PKC activation. We did this using TCR-independent stimulation of TALL-104 human leukemic CTLs. When cells are stimulated with thapsigargin and PMA, agents that increase intracellular Ca 2+ and activate PKC, respectively, PKC-dependent ERK activation is required for lytic granule exocytosis. Expressing a constitutively-active mutant MAP kinase kinase activates ERK independent of PKC. However, activating ERK without PKC does not support lytic granule exocytosis, indicating that there are multiple effects of PKC required for granule exocytosis.

Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius‐A2 catecholaminergic neurons

“…Present findings suggest that this function of PKC is MEK-independent and would act on ERK 1/2 directly. As ERK 1/2 activation induces CREB phosphorylation, this pathway offers an alternative route to the classical pathways involving the direct phosphorylation of CREB by protein kinase A. PKC seems to be able to reach ERKs even through pathways that by-pass Raf and MEK activation, which agree with previous findings showing that there may be mitogen-activated protein kinaseindependent routes of PKC-dependent ERK activation, including direct phosphorylation of ERK by PKC (Grammer and Blenis 1997;Pores-Fernando et al 2008).…”

Calcium influx and signaling in cytotoxic T‐lymphocyte lytic granule exocytosis

“…Interestingly, PI3K activation is not required when TCR‐independent stimuli are used to trigger exocytosis (75). Activation of mitogen‐activated protein kinases (MAPKs) of the extracellular signal regulated kinase (ERK) family is also required (63, 75–77) and occurs by a mechanism that depends in part on PKC activity but also involves other pathways (77–79), perhaps ras‐dependent signaling initiated by Vav, as has been shown to be the case in Th cells (80). Ultimately, cytotoxicity thus requires at a minimum the activity of PKC, ERK, PI3K, and Ca 2+ influx (5).…”

No Specific Subcellular Localization of Protein Kinase C Is Required for Cytotoxic T Cell Granule Exocytosis

“…ERK MAP kinase activation is also required (3)(4)(5), and PI3-kinase activation is required for TCRdependent but not TCR-independent granule exocytosis (6). PKC activation is important for activating ERK, but also plays other, as yet undefined, roles (7).…”