ABSTRACT
Figure 17.1 The Raf/MEK/ERK signaling pathway. The RAF family of serine/threonine kinases has three isoforms, ARAF, BRAF, and CRAF. While ARAF and CRAF require both activation by RAS and phosphorylation, BRAF’s N-terminus is constitutively active, needing only RAS and thus fewer steps for activation [18]. Once activated, RAF can then sequentially stimulate MEK1 and MEK2, which then turn on ERK1 and ERK2. These proceed to activate the cytoplasm targets or travel to the nucleus to finally phosphorylate transcription factors [19-21]. Specifically, the structure of MEK 1/2 with their proline-rich segments in the carboxyl-terminal is thought to play a role in the
activation by RAF [15]. The RAF/MEK interaction is required for the phosphorylation of ERK1/2, which is crucial to cell cycle progression through the G1/S phase [22]. While activation of ERK 1/2 is dependent on the adhesion to the extracellular matrix, the BRAF V600E mutation forgoes this step. Therefore, ERK 1/2 is able to be activated without the ECM and the constitutively activated mutated BRAF allows for up regulated progression through the cell-cycle [23]. Constitutive activity in the Ras/Raf/MEK/ERK MAPK pathway contributes to the oncogenic phenotype of melanoma through its effects on cell proliferation, invasion and survival.
