The extracellular signal-regulated kinase (ERK) cascade is a central pathway that transmits signals from many extracellular agents to regulate cellular processes such as proliferation, differentiation and cell cycle progression. The signaling via the ERK cascade is mediated by sequential phosphorylation and activation of protein kinases in the different tiers of the cascade.

The extracellular signal-regulated kinase (ERK) cascade is a signal transduction pathway that transmits signals from extracellular stimuli such as growth factors, hormones, neurotransmitters and others. Upon interaction with membranal receptors, the signals of extracellular ligands are transmitted via various mechanisms to their appropriate sites of action. is an upstream component of hippocampal MAPK activation during associative learning, since blockade of NMDA receptors by pre-training administration of the NMDA receptor antagonist MK801 blocked ERK activation and reduced both cue and contextual associative learning. Furthermore, inhibition of ERK by pre-training or immediate post-training administration of a MEK inhibitor blocked cue and contextual learning in a dose dependent manner. Additional studies confirmed that the ERK cascade is required for long-term fear memory, as inhibitors of ERK activation caused blockade of memory formation upon testing. The initial findings by Atkins et al. were confirmed and expanded using, in the rat, intraventricular injection and intra-amygdalar infusion, and, in the mouse, systemic administration of an inhibitor of ERK activation. Interestingly, other authors found that fear conditioning caused a transient and significant activation of both ERK1 and ERK2 isoforms 60 min after training in the basolateral amygdala. The authors asserted that the increased activation of both isoforms was specifically associated with the pairing of tone and shock. Pretraining inhibition of ERK dose-dependently impaired LTM of Pavlovian fear conditioning, leaving short-term memory (STM) intact. Transgenic mice expressing dominant-negative MEK1 exhibited decreased ERK 1/2 activity in the hippocampus and a significant impairment in contextual fear conditioning compared with wild-type littermates. These findings further demonstrate that the MEK 1/ERK 1/2 cascade within neurons plays an important role in the processes of learning and memory.

ERK1/2 as regulators of cardiac hypertrophy

Despite the wealth of studies on the subject, the precise role of ERK1/2 as necessary mediators of cardiac hypertrophy is unproven. ERK1/2 become activated in cardiac myocytes in response to G protein-coupled receptor agonists (angiotensin II, endothelin-1, and adrenergic receptors), receptor tyrosine kinase agonists (insulin-like growth factor, and fibroblast growth factor receptors), cytokines, reactive oxygen species, and stretch. The vast majority of research conducted to date aimed at establishing causation between ERK1/2 signaling and the hypertrophic response has been conducted in cultured neonatal rat primary cardiomyocytes. Unfortunately, these previous studies have yielded largely conflicting results, although we will not further discuss the issues surrounding them or the limitations inherent in cultured neonatal myocytes, given previous in-depth reviews on the topic.


Giovannini, M. G. (2006). The role of the extracellular signal-regulated kinase pathway in memory encoding. Reviews in the neurosciences, 17(6), 619-634.

Kehat, I., & Molkentin, J. D. (2010). Extracellular signal‐regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Annals of the New York Academy of Sciences, 1188(1), 96-102.

Yoon, S., & Seger, R. (2006). The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth factors, 24(1), 21-44.

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