The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells

The mitogen-activated protein (MAP) kinase extracellular-signal-regulated kinases (ERKs) are activated by diverse mechanisms. These include ligation of receptor tyrosine kinases such as epidermal growth factor (EGF) and cell adhesion receptors such as the integrins. In general, ligand binding of these receptors leads to GTP loading and activation of the small GTPase Ras, which recruits Raf to the membrane where it is activated. Raf subsequently phosphorylates the dual specificity MAP/ERK kinase (MEK1/2) which in turn phosphorylates and thereby activates ERK. ERK is a promiscuous kinase and can phosphorylate more than 100 different substrates. Therefore activation of ERK can affect a broad array of cellular functions including proliferation, survival, apoptosis, motility, transcription, metabolism and differentiation. ERK activity is controlled by many distinct mechanisms. Scaffold proteins control when and where ERK is activated while anchoring proteins can restrain ERK localization to specific subcellular compartments. Meanwhile, phosphatases dephosphorylate and inactivate ERK thereby shutting off the pathway. Finally, several feedback mechanisms have been identified downstream of ERK activation. Here we will focus on the diverse mechanisms of ERK regulation in mammalian cells.