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 ERK Signaling

Extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) are often referred to together as ERK1/2. ERK1/2 are pleiotrophic mitogen activated serine/threonine protein (MAP) kinases with over 160 known substrates, found throughout the cell, that include other protein kinases, membrane receptors, cytoskeletal proteins, downstream effector kinases and transcription factors. The ERK1/2 substrates share the consensus motif X-Pro-Xaan-Ser/Thr-Pro-X. ERK1/2 regulates proliferation, differentiation, cell cycle processes, and survival, as well as many other cell processes. Excessive ERK1/2 activation induces apoptosis. Many of the oncogenic effects of Ras-GTPases are mediated through ERK1/2 activation.

The central ERK1/2 activation pathway initiates with the activation of MAP3 kinases such as Raf-1 and/or B-Raf (BRAF) by specific Ras-GTPases that are activated by specific GEFs such as EPAC and SOS. EPACs are activated by cAMP and SOS(s) are down-stream effectors of receptor tyrosine kinase (RTK) activation. Rap1-GTPase activates B-Raf and inhibits Raf-1 activation by Ras-GTPase. Activation of Raf-1 and/or B-Raf leads to the activation of the MAP2 kinases, MEK1 and MEK2 (MEK1/2), which in turn activate ERK1/2. ERK1/2 differentially phosphorylates several members of the 90-kDa ribosomal S6 kinase (pp90rsk) (RSK) family including RSK1, RSK2, MNK1/2 and MSK1/2. Together ERK1/2 and the RSKs activate a plethora of transcription factors including but not limited to CREB, c-Myc, c-Jun, c-Fos, and STAT.