Ras Signaling Pathway

The RAS family of GTPases (HRAS, NRAS, and KRAS) comprises proteins that are highly conserved across species and has key roles in numerous basic cellular functions, including control of proliferation, differentiation, and apoptosis. Many of these Ras mediated signals are interpreted differently depending on the cell type or microenvironment receiving the stimulus. Not all of these effectors are activated in any given cell type. The first RAS effector pathway identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis. The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane. The second best-characterized RAS effector family is phosphoinositide 3-kinases (PI3Ks). PIP3 stimulates the AKT/PKB kinase and several of the Rac-GEF’s such as Sos1 and Vav. AKT activation inhibits apoptosis by inhibiting the actions of Bad, Caspase9 and AFX. AKT further hinders apoptosis by phosphorylating the IkB repressor of NFkB. This pathway plays important roles as mediators of RAS-mediated cell survival and proliferation.