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E-Letters

Perspectives:
Emerging Role for ERK as a Key Regulator of Neuronal Apoptosis
Eric C. C. Cheung and Ruth S. Slack (21 September 2004)
Sci. STKE 2004 (251), pe45-pe45. [DOI: 10.1126/stke.2512004pe45]
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Role of ERK in Neuronal Survival and Death

Role Of ERK In Neuronal Survival and Death: Comment on Cheung and Slack, Sci. STKE 2004, pe 45 (2004)

Luca Colucci-D’Amato*1,2, Carla Perrone-Capano2,3, Umberto di Porzio2
1Institute of Endocrinology and Experimental Oncology, CNR, Naples, 2Institute of Genetics and Biophysics, CNR, Naples, 3University of Catanzaro Magna Grecia, Roccelletta di Borgia, Italy

*Corresponding author. E-mail, ludamato@unina.it

We wish to comment on the interesting review by E.C.C. Cheung and R. Slack “Emerging role for ERK as a key regulator of neuronal apoptosis” (1), on the role of ERK in neuronal death.

In neurons, ERK (extracellular signal-regulated kinase), a regulator of many cellular processes, has classically been regarded as a molecule involved in pathways promoting differentiation and/or survival, consistent with its role in signaling pathways downstream of most neurotrophic factors.

In their review, Cheung and Slack focus on the recent view of ERK’s role in neuronal degeneration. They stress that “the question (is) of how ERK activation can bring about such a diverse spectrum of cellular responses, ranging from proliferation to differentiation to apoptosis.” They provide various explanations that account for the various actions exerted by ERK with respect to different cellular functions, namely survival versus apoptosis in neural cells.

In accordance to Cheung and Slack, we would like to stress the role of chronic activation of ERK in neurodegeneration and suggest a model that could explain the apparent paradox of the dual role of ERK, as previously described in our recent review (2) In our paper we proposed that the shift from acute (or phasic) to chronic activation of ERK may lead ERK to shift from a survival factor to a death-promoting factor. The change in ERK kinetics is accompanied by a change in its subcellular localization, the latter being essential for the shift in ERK function. Based on the work of various laboratories, we proposed that the dual specificity phosphatases, MKPs (mitogen-activated protein kinase phosphatases), which selectively dephosphorylate MAPK (mitogen-activated protein kinase), might provide a link between chronic activation of ERK and its altered localization. In addition to their role in controlling ERK phosphorylation status, MKPs strongly bind ERK and may represent possible ERK anchor proteins. MKPs can play an important role in localizing ERK in the cytoplasm or in the nucleus and such cellular targeting could be affected by the kinetics of ERK activation. Indeed, long- and short-term activation of ERK induces high and low levels of MKPs transcription, respectively. The levels of MKPs, in turn, affect the targeting of ERK within the cell and thereby its activity.

 Proposed cascade leading to ERK's physiological or pathological effects.

Fig 1. Proposed cascade of events leading to ERK's physiological or pathological effects. (Top) Stimuli that lead to acute activation of ERK result in labile binding to anchor proteins (MKPs) and transient changes in ERK subcellular compartmentalization (i.e. cytoplasmic-nuclear shift) ultimately leading to physiological effects. (Bottom) Stimuli that lead to chronic activation of ERK result in stable binding to anchor proteins (MKPs) and thereby altered the ERK subcellular compartmentalization, ultimately leading to pathological effects.

References

1. E.C.C. Cheung, R. Slack, Emerging role for ERK as a key regulator of neuronal apoptosis. Sci. STKE 2004, pe 45 (2004).

2. L. Colucci-D'Amato, C. Perrone-Capano, U. di Porzio, Chronic activation of ERK and neurodegenerative diseases. Bioessays 25,1085-1095 (2003).



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