Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke

Abstract

Extracellular signal-regulated kinase 1/2 (ERK1/2), one of the best-characterized members of the mitogen-activated protein kinase (MAPK) family, mediates a range of activity from metabolism, motility, and inflammation to cell death and survival. It is phosphorylated and activated through a three-tiered MEK mode via cell surface receptors stimulated by growth factors or cytokines. The phosphorylated ERK1/2 level is usually increased after cerebral ischemia/reperfusion, but whether an increase in ERK1/2 phosphorylation is protective or detrimental is highly debatable. Much of the support for ERK1/2's role as a neuroprotectant against stroke stems from its apparent involvement in the beneficial effects of growth factors, estrogen, preconditioning, and hypothermia on the ischemic brain. Conversely, evidence supporting the detrimental effects of ERK1/2 activity is derived from its activation promoting inflammation and oxidative stress and its inhibition reducing ischemic damage. The dual potential of ERK1/2 actions in the ischemic brain is likely related to its responses to a diverse array of agonists and cell surface receptors. Plausibly, the ERK1/2 activity generated by cytokines and free radicals or other inflammatory factors after stroke may worsen ischemic damage, whereas the ERK1/2 activity produced by exogenous growth factors, estrogen, and preconditioning favors neuroprotection. Future experiments should be conducted to optimize the protective effect of ERK1/2 while blocking its detrimental actions.

Prokineticin 2 is an endangering mediator of cerebral ischemic injury

“…Interestingly, after excitotoxicity or OGD, PK2 treatment increased both pErk1,2 and pSAP/JNK MAPK levels, but no changes were detected in pAkt levels. Because of the dual role of Erk1,2 and the endangering role of SAP/JNK (44,47), these results suggest that PK2 activates differential signaling during insult conditions, and PK2's effects on pErk1,2 and pSAP/JNK may contribute in part to its deleterious effects in ischemic injury. Further studies are required to understand fully the mechanism by which PK2 exacerbates ischemic injury.…”

“…However, it is unclear whether these pathways also are activated by PK2 during insult. Although Erk1,2 and Akt signaling have been associated mostly with beneficial effects such as promoting cell survival and proliferation (41)(42)(43), they also can exert deleterious effects (44)(45)(46). For example, Erk1,2 generated from cytokines and free radicals can increase ischemic damage (44).…”

“…Although Erk1,2 and Akt signaling have been associated mostly with beneficial effects such as promoting cell survival and proliferation (41)(42)(43), they also can exert deleterious effects (44)(45)(46). For example, Erk1,2 generated from cytokines and free radicals can increase ischemic damage (44). Similarly, Akt phosphorylation in astrocytes can cause vascular leakage in ischemic brain (45), and Akt1 has been demonstrated to mediate leukocyte migration and acute inflammation (46).…”

Notch signaling in the brain: In good and bad times

“…Interestingly, a recently identified neuroprotective gene, Botch (Dai et al, 2010), can regulate Notch expression (Chi et al, 2012). Similar dual functions have also been described for another pathway: PIK3/AKT (Brown, 2007;Sawe et al, 2008), which has been intimately connected to Notch in the survival/death choice in cancer (Calzavara et al, 2008;Chan et al, 2007;Gutierrez and Look, 2007;Palomero et al, 2007).…”

Neuronal nicotinic receptors as novel targets for inflammation and neuroprotection: mechanistic considerations and clinical relevance

“…Extracellular signal-regulated kinase 1/2 (ERK1/2), one of the most characterized members of the MAPK family, mediates a range of activities from inflammation to cell death and survival. It has been argued that ERK1/2 activity generated by endogenous inflammatory factors may have detrimental effects, whereas ERK1/2 activity produced by exogenous signals (eg, growth factors) favors neuroprotection [87] . Various additional strategies for neuroprotection have been used to attenuate brain inflammation via control of proliferation and production of proinflammatory cytokines, including derivatives of the insulin-like growth factor-1 [88] and adenosine A2A analogues [89,90] .…”