title: Intracellular activation of EGFR by fatty acid synthase dependent palmitoylation.
abstract: 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.
authors.affiliation: Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas, USA.
authors.forename: Lakshmi Reddy
authors.initials: LR
authors.lastname: Bollu
authors.affiliation: Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas, USA.
authors.forename: Rajashekhara Reddy
authors.initials: RR
authors.lastname: Katreddy
authors.affiliation: Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas, USA.
authors.forename: Alicia Marie
authors.initials: AM
authors.lastname: Blessing
authors.affiliation: Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas, USA.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Pham
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Baohui
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas, USA.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Weihua
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D042541:Intracellular Space / Q000201:enzymology; D054878:Lipoylation; D009369:Neoplasms / Q000378:metabolism*; D014162:Transfection
chemical_list: C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; cancer; fatty acid synthase; palmitoyl transferases; palmitoylation