p66Shc-dependent apoptosis requires Lck and CamKII activity

Abstract

p66Shc, an adaptor molecule which enhances reactive oxygen species (ROS) production by mitochondria, promotes T-cell apoptosis by inducing mitochondrial dysfunction and impairing Ca(2+) homeostasis. We have addressed the potential role of Lck, a kinase which has been implicated in T-cell apoptosis induced by a number of stimuli, in the proapoptotic activity of p66Shc. Lck deficiency in Jurkat T cells overexpressing p66Shc leads to impaired apoptotic responses to supraphysiological increases in [Ca(2+)](c). This defect could be rescued by reconstitution of Lck expression, indicating that Lck is required for p66Shc-dependent apoptosis. Furthermore, p66Shc phosphorylation on serine 36 (S36), an event on which the proapoptotic function of p66Shc depends, requires Lck. p66Shc-dependent mitochondrial dysfunction, altered Ca(2+) homeostasis and S36 phosphorylation require moreover the activity of CaMKII, a Ca(2+)/calmodulin-dependent kinase known to be implicated in the proapoptotic activity of Lck in T cells. The results suggest that increases in [Ca(2+)](c) lead to CaMKII activation and subsequent Lck-dependent p66Shc phosphorylation on S36. This event causes both mitochondrial dysfunction and impaired Ca(2+) homeostasis, which synergize in promoting Jurkat T-cell apoptosis.

The Glycerophosphoinositols: From Lipid Metabolites to Modulators of T-Cell Signaling

“…Given the central role of Lck as the initiator kinase in TCR signaling (37), it can be hypothesized that GroPIns4 P has the ability to modulate T-cell activation. Lck has also been implicated in the regulation of T-cell apoptosis induced by a wide range of stimuli, including prolonged TCR stimulation (45) and treatment with sphingosine (46), and it is also an essential component of the signaling pathways that control Ca 2+ -mediated T-cell apoptosis, which involve both the conformational activation of Bax and the expression of proapoptotic Bcl-2 family members (47). How TCR engagement can lead to cell fates as diverse as activation, anergy, and apoptosis is one of the fundamental and as yet open questions in immunology.…”

Baicalin alleviates ischemia-induced memory impairment by inhibiting the phosphorylation of CaMKII in hippocampus

“…CaMKII, a multifunctional heteromeric serine/threonine protein kinase, is activated by both Ca 2+ and oxidative stress (Erickson et al, 2008). Increases in CaMKII activity have been reported to correlate with cell apoptosis, myocardial ischemia/reperfusion injury and cell excitotoxic insult (Ling et al, 2013;Patrussi et al, 2012) . Our results suggested that baicalin mediated a protective effect by preventing inhibition of neuronal death from apoptosis through regulation of [Ca 2+ ] i and further attenuating the phosphorylation level of CaMKII in hippocampal neurons.…”

Regulation of Selective B Cell Autophagy by the Pro-oxidant Adaptor p66SHC

“…In addition to its ability to inhibit survival signaling at multiple levels, p66SHC increases the susceptibility of lymphocytes to cellular stress, promoting apoptosis (Pellegrini et al, 2007;Capitani et al, 2010). Pharmacological or physiological apoptotic stimuli induce p66SHC phosphorylation on S36 through a mechanism requiring Ca 2+ calmodulin-dependent kinase and the tyrosine kinase LCK (Pacini et al, 2004;Patrussi et al, 2012). S36-phosphorylated p66SHC promotes apoptosis by impairing both mitochondrial function and Ca 2+ homeostasis (Pellegrini et al, 2007).…”