H Ras, K Ras, and N Ras perform as molecular switches when an inactive Ras GDP is converted into an energetic Ras GTP. In its GTP bound form, Ras recruits and activates Raf kinases. The activated Raf kinases interact and activate MEK 1/2, which in flip catalyze the phosphorylation of threo nine and tyrosine residues within the activation sequence Thr Glu Tyr of ERK1/2. Unlike Raf and MEK 1/2 kinases which have narrow substrate specificity, ERK1 and ERK2 have a wide range of cytosolic and nuclear sub strates. Activated ERKs can translocate into the nucleus to initiate diverse cellular responses, which include cell prolifera tion, survival, differentiation, motility, and angiogenesis. As an illustration, ERK1/2 signaling promotes the progression of cells in the G0/G1 to S phase by activation of constructive cell cycle regulators cyclin D1 and c Myc, and down regulation of anti proliferative proteins which include Tob1, FOXO3a and p21.
Similarly the Raf/MEK/ ERK MAP kinase pathway promotes cell survival by blocking NF kB, major to enhanced transcription of anti apoptotic and pro survival genes like Bcl two and Mcl 1. The Ras/Raf/MEK/ERK signaling is activated in hu man cancers via several different mechanisms. Elevated ERK top article 1/2 signaling is often resulting from direct mutational activa tion or amplification of genes encoding crucial elements with the Ras/Raf/MEK/ERK pathway for instance Ras and B Raf. A significant scale cancer genome sequencing study revealed that B Raf is mutated in about 20% of all cancers and in far more than 60% of melanomas. Significantly less usually ERK 1/2 cascade may also be activated by MEKs in reliable tumors like melanoma, colon, and lung carcinomas. MEK3 and MEK6 are functionally very similar and encoded by MAP2K3 and MAP2K6 genes, respectively. The genes are each positioned on chromosome 17q.
MEK3 and MEK6 include 347 and 334 amino acids residues re spectively. Structurally MEK6 differs from MEK3 in terms of C and N terminal areas. Nonetheless, the ATP binding web sites, and serine/threonine and tyrosine catalytic web sites are conserved. MEK3/6 signaling pathway is activated by growth element stimulation via RTKs. Additionally, the cascade can also be activated by G protein coupled receptors, intracellular receptors, and toll SCH 900776 ic50 like receptors, in response to a lot of stimuli such as physical and chemical stresses, hormones, UV irradiation, and cytokines, like interleukin 1 and tumor necrosis element. These stimuli activate various MAPK kinase kinases, which include things like TAK1, ASK1/2, DLK, MEKK4, TAO1/2/3 and MLK2/3. Active MAPKKKs phosphorylate and activate MEK3/6, which in flip catalyzes the concomitant phosphorylation of the threonine/serine plus a tyrosine residue within the p38 MAPK. MEK6 activates every one of the 4 isoforms of p38 MAP kinase whereas MEK3 can only activate p38 and p38B isoforms.