BRAFV600E Negatively Regulates the AKT Pathway in Melanoma Cell Lines

摘要: Cross-feedback activation of MAPK and AKT pathways is implicated as a resistance mechanism for cancer therapeutic agents targeting either RAF/MEK or PI3K/AKT/mTOR. It thus important to have better understanding the molecular mechanisms improve patient survival benefit from these agents. Here we show that BRAFV600E negative regulator pathway. Expression in NIH3T3 cells significantly suppresses MEK inhibitor (RG7167) mTORC1 (rapamycin) induced phosphorylation (pAKT) downstream signal activation. Treatment-induced pAKT elevation found BRAF wild type melanoma but not subset cell lines harboring BRAFV600E. Knock-down elevates basal signals, whereas knock-down CRAF, MEK1/2 ERK1/2 treatment with no impact on pAKT. Mechanistically, interacts rictor complex (mTORC2) regulates through mTORC2. identified mTORC2 after immunoprecipitation rictor. abrogates depletion enhances cellular enzyme activity Aberrant pathway by PTEN loss appears override Taken together, our findings suggest cells, negatively rictor-dependent, MEK/ERK kinase-independent manner. Our study reveals novel underlying regulation feedback loops between pathways.