Extracellular-signal-regulated kinases (ERKs; EC 2.7.11.24) are members of the larger family of mitogen-activated protein kinases (MAPKs) that includes ERK5, the c-Jun N-terminal protein kinases (JNKs) and the p38 MAP kinases, and transduce extracellular signals from cell surface receptors to the cell nucleus. The activation of ERK is coupled to stimulation of cell surface receptors via several different upstream signaling pathways, and plays critical roles in the regulation of gene expression and cell proliferation. The canonical ERK MAP kinase cascade (see section of kinases involved in MAPK/ERK signaling) is stimulated upon the binding of extracellular growth factors such as EGF and PDGF to their respective transmembrane receptor tyrosine kinases (RTKs). The subsequent auto-phosphorylation of the cytoplasmic tails of the receptor on tyrosine leads to the recruitment of Grb-2, which binds the guanine exchange factor SOS. Recruitment of SOS to the membrane promotes its interaction with the membrane localized small GTPase Ras and results in GTP loading and activation of Ras. This is followed by the sequential recruitment and activation of the kinases Raf, MEK, and ERK. Upon activation, MEK phosphorylates ERK, leading to dissociation and dimerization of ERK and subsequent translocation into the nucleus. In the nucleus ERK may phosphorylate many substrates including transcription factors.