Mitogen Activated Protein Kinase (MAPK) Overview

The mitogen-activated protein kinase (MAPK) pathway mediates signal transduction from cell surface receptors to downstream transcription factors that lead to cellular responses such as cell proliferation, growth, motility, survival and apoptosis.¹ The role of MAPK pathway in cancer, immune disorders and neurodegenerative diseases has been well recognized.² There are three major classes of MAPKs. Extracellular signal-regulated kinases (ERK1/2), mediate growth factor receptor, (e.g. epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF) receptor cMET) and G-protein coupled-receptor (GPCR) signaling through Ras-Raf-MAPK kinase pathway.^3,4 The other two classes of MAPKs, c-Jun N-terminal kinases (JNK1, JNK2 and JNK3) and p38 kinases (α, β, γ, δ), mediate stress-induced signaling events (e.g. IL-1 stimulation, TNFα stimulation, and UV radiation) that lead to apoptosis.⁵ Activation of these MAPKs leads to the phosphorylation and activation of downstream transcription factors (e.g. the activator protein 1 (AP1) family (c-fos and c-jun)), which then binds to its DNA response elements and regulates downstream gene expression. Components of these various MAPK signaling pathways have been investigated as therapeutic targets for various disease areas. For example, EGFR has been a well sought target for non-small cell lung cancer³ and cMET, as a target for tumor growth and metastasis.⁴ Both JNK and p38 have been pursued as targets for developing therapies for inflammatory and neurodegenerative diseases.⁵

In addition to canonical signaling through growth-factor receptors, mitogenic singnaling can also be activated via G-protein-coupled-receptor (GPCR) agonism. This mechanism can be mediated via secondary-messenger signaling (Gα-protein-dependent) as well as mechanisms mediated by Gα-protein independent pathways (such as β-arrestin or Gβ/γ subunits).