Abstract

ROLE OF RAS-RAF-MEK-ERK MITOGEN ACTIVATED PROTEIN KINASE IN THE DEVELOPMENT OF CANCER

*S. M. Fazla Rabby

ABSTRACT

Proliferation, survival, differentiation and motility of cancer cells are controlled by different intracellular signaling pathways. Among these, the act of the RAS/ RAF/ MAP kinase kinase (MEK)/ extracellular-signal-regulated kinase (ERK) (MAPK) pathway in the pathogenesis of human carcinoma is the most important one. Ligands upon binding to the extracellular domain of EGFR results in homodimerization or heterodimerization of the receptor, triggering the activation of tyrosine kinase and signaling cascades initiation including RAS. The GRB2/SOS complex at the inner face of the plasma membrane promotes the interaction of membrane-associated RAS with SOS facilitating RAS activation. GTP-bound RAS triggers different signaling pathways including the RAF/MEK/ERK cascade. Through these pathways RAS controls & regulates cell proliferation, survival and other aspects of cell behavior that are able to contribute to the transformed phenotype. Mutation and amplification of EGFR gene resulting in the overexpression of receptors; somatic and point mutations in the RAS family genes compromising the GTPase activity of RAS causing RAS accumulation in the GTP-bound, active form; RAF mutation (mainly BRAF) resulting in the deletion of tumor suppressor gene PTEN-- result in the constitutive activation of the MAPK pathway. Constitutively active form of ERK promotes the degradation of pro-apoptic BIM, BAD proteins and causes overexpression of pro-survival BCL-2 proteins specially MCL-1 and disrupts cell-matrix interactions resulting in the development of tumor cells. Eventually Over-activated ERK helps tumor cell migration by mediating kinases and enzymes such as MLCK, Calpain, FAK, and Paxillin.

Keywords: RAS, RAF, MEK, ERK, MAPK, Tumor.