Download RAS (overview) Midwest 2013

Ras Activates a MAPK Cascade
Hong Joo Kim & Dafna Bar-Sagi, 2004
The Ras mitogen-activated protein kinase (MAPK) cascade, including Raf, Mek and Erk, is a
ubiquitous signaling module that couples receptor-mediated events at the cell surface to
cytoplasmic and nuclear effectors. The Ras MAPK cascade is perhaps best known for its crucial
role in mediating the transduction of signals from receptor tyrosine kinases. Growth factor
binding to receptor tyrosine kinases induces receptor dimerization and cross phosphorylation to
initiate transduction of the signal into the cell. The phosphorylated receptor dimer in turn leads to
the activation of the small GTPase Ras. This step is accomplished by the recruitment of a protein
complex consisting of the Ras exchange factor son-of-sevenless (SOS) and the growth-factorreceptor bound protein-2 (GRB2) to a phosphate docking site on the receptors themselves. SOS
activates Ras by promoting the exchange of GTP for GDP placing Ras in the active GTP bound
conformation. Activated Ras triggers a signal-relay mechanism starting with the activation of Raf.
Activated Raf then phosphorylates Mek leading to its activation. Subsequently, activated Mek
catalyses the phosphorylation of Erk. In the final step, phosphorylated Erk translocates to the
nucleus where it phosphorylates and activates transcription factors that control the expression of
genes that are required for cell growth, differentiation and survival. Importantly, overactivation of
the Ras MAPK pathway can lead to cancer (uncontrolled cell proliferation).