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Front. Biol.    2014, Vol. 9 Issue (2) : 95-103    https://doi.org/10.1007/s11515-014-1299-x
REVIEW
Growth arrest signaling of the Raf/MEK/ERK pathway in cancer
Jong-In PARK()
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
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Abstract

The Raf/MEK/extracellular signal-regulated kinase (ERK) pathway has a pivotal role in facilitating cell proliferation, and its deregulated activation is a central signature of many epithelial cancers. However paradoxically, sustained activity of Raf/MEK/ERK can also result in growth arrest in many different cell types. This anti-proliferative Raf/MEK/ERK signaling also has physiological significance, as exemplified by its potential as a tumor suppressive mechanism. Therefore, significant questions include in which cell types and by what mechanisms this pathway can mediate such an opposing context of signaling. Particularly, our understating of the role of ERK1 and ERK2, the focal points of pathway signaling, in growth arrest signaling is still limited. This review discusses these aspects of Raf/MEK/ERK-mediated growth arrest signaling.
Keywords Raf      MEK1/2      ERK1/2      proliferation      growth arrest      non-kinase effect     
Corresponding Author(s): Jong-In PARK   
Issue Date: 13 May 2014
 Cite this article:   
Jong-In PARK. Growth arrest signaling of the Raf/MEK/ERK pathway in cancer[J]. Front. Biol., 2014, 9(2): 95-103.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-014-1299-x
https://academic.hep.com.cn/fib/EN/Y2014/V9/I2/95
Fig.1  A conceptual model for tumor suppressive signaling of Raf/MEK/ERK. Oncogenic alterations leading to aberrant activation of Raf/MEK/ERK can direct the pathway signaling to mediate growth arrest. Progression of tumorigenesis requires inactivation of this tumor suppressive response. In the absence of this mechanism, deregulated Raf/MEK/ERK activity is exploited to stimulate uncontrolled cell growth.
Fig.2  Two different thresholds of Raf/MEK/ERK activity determine cell fate to proliferation or growth arrest. In this model, not only too low but also too high Raf/MEK/ERK activity restricts cell proliferation. Different cell types may maintain different extent of pathway activity between these thresholds, displaying heterogeneous sensitivity to pathway activity.
Fig.3  Regulation of p21CIP1 contrasts ERK1/2 function in the opposing contexts of Raf/MEK/ERK signaling, i.e., proliferation versus growth arrest. To promote cell proliferation, ERK2 phosphorylates Thr57 and Ser130 of p21CIP1, which induces p21CIP1 ubiquitination and subsequent proteasomal degradation. In contrast, to promote growth arrest, ERK1/2 upregulates p21CIP1 levels in cells for which ERK1/2 has non-kinase effects. These kinase versus non-kinase effects of ERK1/2 on p21CIP1 highlight different mode of ERK1/2 signaling for the opposing physiological outputs.
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