MAP Kinase Pathway

Mitogen-activated protein kinases (MAPK) are proteins that are serine/ threonine specific kinases which are activated by a wide range of stimuli including proinflammatory cytokines, growth factors, mitogens, osmotic stress, heat shock etc. These proteins function in a signaling cascade are activated upon ligand binding to a cell surface receptor activating several MAP/ER kinases, which in turn phosphorylate their respective substrates. These events thereby regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.
Upon the extracellular mitogen binding to the ligand, Ras a GTPase exchanges GDP for GTP. This in turn initializes a cascade activating MAP3K (Raf) which in turn activates MAP2K which activates MAPK. This MAPK can activate a number of transcription factors which control key processes in the cell.
For example epidermal growth factor (EGF) binds the EGFR which activates the tyrosine kinase activity of the EGFR (receptor). Grb2 and SH2 domain containing proteins recognize phosphorylated residues along with a guanine nucleotide exchange factor SOS, and binds to the EGFR. GDP is then swapped for GTP which binds Ras to make it active. Ras activates Raf which can phosphorylate and activate MEK1 and MEK2 which in turn activate MAPK. MAPK regulates a number of transcription factors including c-myc, CREB, C-Fos etc. All these regulate expression of a number of genes involved in apoptosis, differentiation, cancer etc. Defects in the regulation of this pathway can lead to uncontrolled growth in cells,leading to cancer. Over the last decade, important advances have been made in developing novel agents that modulate key proteins in this pathway culminating in the approval by the FDA of Sorafenib (Nexavar® ) for the treatment of advanced renal carcinoma. Therapeutic advances in this area should continue for many years to come.