Ras Protein and MAPK Pathway | Cell Signaling |Biology

After reading this article you will learn about the Ras protein and MAPK pathways that regulates various cellular activities.

The gene family ras encodes small GTPases that are involved in cellular signal transduction. Ras the super-family of proteins regulates diverse cell behaviors such as cell growth, differ­entiation and survival. Since Ras communicates signals from outside the cell to the nucleus, mutations in ras genes can permanently activate it and cause inappropriate transmission inside the cell even in the absence of extracellular signals. Because these signals result in cell growth and division, disregulated Ras signaling can ultimately lead to oncogenesis and cancer.

Ras proteins function as binary molecular switches that control intracellular signaling networks. Ras-regulated signal pathways control processes such as actin- cytoskeletal integ­rity, proliferation, differentiation, cell adhesion, apoptosis, and cell migration. Ras and Ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis. Activated Ras activates the protein kinase activity of RAF kinase. RAF kinase phosphorylates and activates MEK. MEK phosphorylates and activates a mitogen-activated protein kinase (MAPK).

Mitogen-activated protein (MAP) kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli (mitogens, osmotic stress, heat shock and pro-in­flammatory cytokines) and regulate various cellular activities, such as gene expres­sion, mitosis, differentiation, proliferation, and cell survival/apoptosis. MAPK pathways are activated within the protein kinase cascades called “MAPK cascade”. Each one consists of three enzymes, MAP kinase, MAP kinase kinase (MKK, MEKK, or MAP2K) and MAP kinase kinase kinase (MKKK or MAP3K) that are activated in series. A MAP3K that is acti­vated by extracellular stimuli, which phosphorylates a MAP2K on its serine and threonine residues and this MAP2K activates a MAP kinase through phosphorylation on its serine and tyrosine residues.

The phosphorylation of tyrosine precedes to the phosphorylation of threonine, although phosphorylation of either residue can occur in the absence of the other. Because both tyrosine and threonine phosphorylations are required to activate the MAP kinases, phosphatases that remove phosphate from either sites will inactivate them. This MAP kinase signaling cascade has been evolutionary well-conserved from yeast to mam­mals. Cascades convey information to effectors, coordinates incoming information from other signaling pathways, amplify signals, and allow for a variety of response patterns.

Down-regulation of MAP kinase pathways may occur through dephosphorylation by serine/threonine phosphatases, tyrosine phosphatases, or dual-specificity phosphatases and through feedback inhibitory mechanisms that involve the phosphorylation of upstream kinases. Drugs that selectively down-regulate MAP kinase cascades could prove to be valu­able as therapeutic agents in the control of malignant disease.