Intracellular activation of EGFR by fatty acid synthase dependent palmitoylation
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Lakshmi Reddy Bollu1, Rajashekhara Reddy Katreddy1, Alicia Marie Blessing1, Nguyen Pham1, Baohui Zheng2, Xu Wu2, Zhang Weihua1
1Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas, USA
2Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
Zhang Weihua, e-mail: [email protected]
Keywords: EGFR, fatty acid synthase, palmitoylation, palmitoyl transferases, cancer
Received: May 28, 2015 Accepted: August 31, 2015 Published: September 12, 2015
Epidermal growth factor receptor (EGFR) is an oncogenic receptor tyrosine kinase. Canonically, the tyrosine kinase activity of EGFR is regulated by its extracellular ligands. However, ligand-independent activation of EGFR exists in certain cancer cells, and the underlying mechanism remains to be defined. In this study, using PC3 and A549 cells as a model, we have found that, in the absence of extracellular ligands, a subpopulation of EGFR is constitutively active, which is needed for maintaining cell proliferation. Furthermore, we have found that fatty acid synthase (FASN)-dependent palmitoylation of EGFR is required for EGFR dimerization and kinase activation. Inhibition of FASN or palmitoyl acyltransferases reduced the activity and down-regulated the levels of EGFR, and sensitized cancer cells to EGFR tyrosine kinase inhibitors. It is concluded that EGFR can be activated intracellularly by FASN-dependent palmitoylation. This mechanism may serve as a new target for improving EGFR-based cancer therapy.
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