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Transcript
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).