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Event Type:  Lecture (This is an NIH Science event)
Title:  Regulation of EGFR Signaling by Protein Palmitoylation in Cancer
Description:  Inappropriate activation of the Epidermal Growth Factor Receptor, EGFR, contributes to a variety of human malignancies. Effective therapeutic targeting of this pathway requires a deeper understanding of its regulation. We recently found that EGFR is palmitoylated on the C-terminal tail and silencing the palmitoyltransferase DHHC20 decreases EGFR palmitoylation and increases EGFR signaling. We identified cysteine residues 1025 and 1034 as palmitoylation sites within the C-terminal tail of EGFR by mass spectrometry. Mutation of cysteine residue 1025 to alanine (EGFRC1025A) is sufficient to increase receptor activation and downstream signaling. The palmitoylated residues are encoded by exons that have been shown to be deleted in lung adenocarcinoma and glioblastoma and the mutant receptors have transforming potential and induce sensitivity to EGFR inhibitors. We also find that decreasing EGFR palmitoylation by silencing DHHC20 or by expressing the EGFRC1025A point mutant increases EGFR inhibitor induced cell death in breast and lung cancer cells. Expression of the EGFRC1025A mutant alone in NIH3T3 cells does not affect cell growth or sensitivity to EGFR inhibitors. However, when EGFRC1025A is expressed in NIH3T3 cells containing activated KrasG12V cell growth is decreased and EGFR inhibitor induced cell death is increased. Our current hypothesis we are exploring is that the increased dependence on EGFR signaling mediated by DHHC20 inhibition is contingent on constitutively activated Ras signaling. In vivo studies are ongoing and preliminary data indicate there is a requirement for DHHC20 for tumor growth in Kras driven lung cancer in mice.
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Tuesday, October 17, 2017   11:30pm - 1:00pm Add To Outlook Calendar     Add To iCal Calendar     Add To Entourage Calendar
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Name:   Eric S. Witze, Ph.D.
Organization:   University of Pennsylvania - Perelman School of Medicine
City/Province:   Philadelphia
State:   Pennsylvania
Country:   USA

Organization(s):  [NIH] National Institute of Child Health and Human Development (NICHD) - CBNB/Unit on Structural and Chemical Biology of Membrane Proteins

Location:  On the main NIH Campus
Building:  Building 37
Room:  6041/6107
Street Address:  37 Convent Drive
City:  Bethesda
State:  Maryland
Zip Code:  20892
Other Information:  6th floor, parking garages near building.

Name:   Anirban Banerjee, Ph.D.
Phone:   301-496-4855
Name:   Lisa Bell-Gonzalez
Phone:   301-402-5340
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