Extracellular Ren stimuli confinement Lich mediated activation of factor growth of receptor tyrosine kinases, result in the recruitment sequential phosphorylation and activation of one of the three isoforms of Ras, Raf three fAmily ben by members of the Src-family tyrosine kinase, MEK 18 20, 21 23 and 23 on ERK ERK.21 translocation into the cell nucleus and the phosphorylation of several nuclear transcription factors in cell proliferation, differentiation and survival CONFIRMS. Constitutive activation of MAPK occurs in 90% of melanomas.24 The two h Most common mechanisms Andarine for activation of MAPK in melanoma mutations in BRAF and NRAS genes.25, 26 The BRAF V600E mutation accounts for approximately 90% of the total activation of BRAF mutations.25 This protein product of the V600E mutation showed an increase of 10.7 times of the kinase activity of t in comparison to the wild type BRAF protein.25 constitutive activation MAPK pathway and a proliferative advantage and survival rate of cancer cell.
27 mutations ARAF and CRAF were not found in melanoma.28 is, 29 is a potent inhibitor of the protein BRAF V600E mutant BRAF vemurafenib activated and wild type is A, and a weak inhibitor of the CRAF isoforms.30 zweith M most frequent opportunities for MAPK activation in melanoma is due to mutations in the RNA gene.26 somatic RAS mutations typically occur in codons 12, 13, or 61 Vargatef and keep RAS protein in a constitutively active state.31 HRAS mutations and KRAS isoforms are rare in melanoma.32 34 Interestingly, BRAF and RAS activating mutations often mutually exclusively end events, suggesting that a mutation in the same manner is sufficient for pathway activation and designating redundant mechanisms of activation of this signaling pathway in the pathogenesis of melanoma.
Interestingly, oncogenic RAS can also bind and activate PI3K, AKT increased activity.35 Hte Sun RAS activation leads to an overexpression of two major signaling pathways in melanoma target PI3K and MAPK / AKT involved / S Ugetieren rapamycin ways. The mechanism of molecular and pathway activation in response to specific targeted inhibition may be important determinants of the receiver Accessibility and the clinical benefit of the individual agents and combinations. The pathway PI3K/Akt/mTOR PI3K/Akt/mTOR pathway is another pathway which aberrantly in several cancers, including normal melanoma.35 is activated in response to RTK activated PI3K phosphorylates phosphatidylinositol bisphosphate 4.5 to 3, phosphatidylinositol 4, 5-triphosphate, the recruitment of other proteins of the plasma membrane and results in the activation of the key downstream effectors of PI3K, AKT.
36 Once activated, phosphorylated AKT f is a number of substrates, which survive rdern cell proliferation and invasion.36 A substrate is mTOR modulates a serine-threonine kinase, protein synthesis, angiogenesis, and cell cycle progression and validated therapeutic target in renal cancer, neuroendocrine tumors, and lymphoma. Although PI3K activation mutations rarely effectors Akt and PTEN are modified in most melanomas.37, 38 are the tumor suppressor gene PTEN encodes a lipid and protein phosphatase that negatively regulates PI3K cascade by dephosphorylation PIP3.39, 40 letters or loss of expression of PTEN function or epigenetic inactivation, inactivation or deletion mutation in 30% to 60% of prime Ren observed melanomas.