Dangerous liaisons: flirtations between oncogenic BRAF and GRP78 in drug-resistant melanomas.
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BRAF mutations in aggressive melanomas result in kinase activation. BRAF inhibitors reduce BRAF(V600E) tumors, but rapid resistance follows. In this issue of the JCI, Ma and colleagues report that vemurafenib activates ER stress and autophagy in BRAF(V600E) melanoma cells, through sequestration of the ER chaperone GRP78 by the mutant BRAF and subsequent PERK activation. In preclinical studies, treating vemurafenib-resistant melanoma with a combination of vemurafenib and an autophagy inhibitor reduced tumor load. Further work is needed to establish clinical relevance of this resistance mechanism and demonstrate efficacy of autophagy and kinase inhibitor combinations in melanoma treatment.
Proto-Oncogene Proteins B-raf
Endoplasmic Reticulum Stress
Published Version (Please cite this version)10.1172/jci74609
Publication InfoShenolikar, Shirish (2014). Dangerous liaisons: flirtations between oncogenic BRAF and GRP78 in drug-resistant melanomas. The Journal of clinical investigation, 124(3). pp. 973-976. 10.1172/jci74609. Retrieved from https://hdl.handle.net/10161/17237.
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Professor Emeritus of Psychiatry and Behavioral Sciences
Protein phosphorylation controls a wide range of physiological processes in mammalian tissues. Phosphorylation state of cellular proteins is controlled by the opposing actions of protein kinases and phosphatases that are regulated by hormones, neurotransmitters, growth factors and other environmental cues. Our research attempts to understand the communication between protein kinases and phosphatases that dictates cellular protein phosphorylation and the cell's response to hormones. Over the