The MAP Kinase Signaling Cascades: A System of Hundreds of Components Regulates a Diverse Array of Physiological Functions

  • Yonat Keshet
  • Rony SegerEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 661)


Sequential activation of kinases within the mitogen-activated protein (MAP) kinase (MAPK) cascades is a common, and evolutionary-conserved mechanism of signal transduction. Four MAPK cascades have been identified in the last 20 years and those are usually named according to the MAPK components that are the central building blocks of each of the cascades. These are the extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-Terminal kinase (JNK), p38, and ERK5 cascades. Each of these cascades consists of a core module of three tiers of protein kinases termed MAPK, MAPKK, and MAP3K, and often two additional tiers, the upstream MAP4K and the downstream MAPKAPK, which can complete five tiers of each cascade in certain cell lines or stimulations. The transmission of the signal via each cascade is mediated by sequential phosphorylation and activation of the components in the sequential tiers. These cascades cooperate in transmitting various extracellular signals and thus control a large number of distinct and even opposing cellular processes such as proliferation, differentiation, survival, development, stress response, and apoptosis. One way by which the specificity of each cascade is regulated is through the existence of several distinct components in each tier of the different cascades. About 70 genes, which are each translated to several alternatively spliced isoforms, encode the entire MAPK system, and allow the wide array of cascade’s functions. These components, their regulation, as well as their involvement together with other mechanisms in the determination of signaling specificity by the MAPK cascade is described in this review. Mis-regulation of the MAPKs signals usually leads to diseases such as cancer and diabetes; therefore, studying the mechanisms of specificity-determination may lead to better understanding of these signaling-related diseases.

Key words

ERK JNK p38 Signaling cascades Phosphorylation 



This work was supported by grants from the Mario Negri–Weizmann collaborative fund and from the EU Sixth Frame­work Program under the SIMAP (IST-2004-027265) and GROWTHSTOP (LSHC CT-2006-037731). RS is an Incumbent of the Yale S. Lewine and Ella Miller Lewine professorial chair for cancer research.


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© Springer Science+Business Meida, LLC 2010

Authors and Affiliations

  1. 1.Department of Biological RegulationThe Weizmann Institute of ScienceRehovotIsrael

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