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: Lakshmi Reddy Bollu, Rajashekhara Reddy Katreddy, Alicia Marie Blessing, Nguyen Pham, Baohui Zheng, Xu Wu, Zhang Weihua
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 33 Pg. 34992-5003 (Oct 27 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26378037 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• FASN protein, human
• Fatty Acid Synthase, Type I
• EGFR protein, human
• ErbB Receptors

Topics

• Blotting, Western
• Cell Line, Tumor
• Enzyme Activation
• ErbB Receptors (metabolism)
• Fatty Acid Synthase, Type I (metabolism)
• Humans
• Immunohistochemistry
• Immunoprecipitation
• Intracellular Space (enzymology)
• Lipoylation
• Neoplasms (metabolism)
• Transfection