Eric S. Witze, Ph.D.

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Associate Professor of Cancer Biology
Assistant Investigator, Abramson Family Cancer Research Institute
Department: Cancer Biology
Graduate Group Affiliations

Contact information
754 Biomedical Research Building II/III
421 Curie Boulevard
Philadelphia, PA 19104-6160
Office: (215)573-6301
Fax: (215)573-6725
Lab: (215)746-3460
B.A. (Biology)
University of California, Santa Barbara, 1994.
Ph.D. (Molecular, Cell, & Developmental Biology)
University of California, Santa Barbara, 2003.
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Description of Research Expertise

Research Interest: Wnt control of cell polarity in cancer.

Key Words: Wnt signaling, cell polarity, cytoskeleton, melanoma, live cell imaging

My lab has focused on the regulation of cell signaling in cancer through protein palmitoylation in response to the non-canonical Wnt signaling pathway. The goal has been to develop a biochemically tractable system to begin to understand how non-canonical Wnt signaling regulates cell polarity Treatment of melanoma cells with purified Wnt5a induces a cell polarity phenotype involving the polarized localization of the cell adhesion molecule MCAM. We discovered that MCAM is palmitoylated and Wnt5a activation induces depalmitoylation. When the palmitoylated cysteine residue is mutated to glycine MCAM asymmetrically localizes independent of Wnt5a treatment. This demonstrated a novel pathway originating with Wnt5a binding and resulting in depalmitoylation of MCAM by the enzyme APT1. We have further shown that Wnt5a signaling induces phosphorylation of APT1 on specific serine residues and this modification increases APT1 activity and metastatic behavior of melanoma cells.

A second focus of the lab involves understanding how the palmitoyl-transferase DHHC20 palmitoylates the epidermal growth factor receptor (EGFR) on the C-terminal tail and suppresses EGFR activation. Inhibition of DHHC20 by shRNA decreases levels of EGFR palmitoylation and increases the amplitude of receptor signaling when stimulated with EGF. We mapped specific palmitoylation sites to cysteine residues in the C-terminal tail. The specific palmitoylation sites that were mapped by mass spectrometry reside in exons 26 and 27 that are sometimes deleted in lung cancer and glioblastoma. Deletion of the exons activate EGFR and can transform NIH3T3 cells. We similarly found that mutating the cysteine residues in exon 26 or 27 also activate EGFR and when expressed can transform cells. We hypothesize that loss of palmitoylation is the cause of receptor activation when exons 26 and 27 are deleted. Furthermore, when the palmitoylated cysteine residues are mutated the downstream MAPK/ERK pathway is activated and cells become dependent on EGFR signaling making cells sensitive to EGFR inhibitors. Unexpectedly, we also found that in lung cancer cells harboring mutations in EGFR that impart resistance to the EGFR inhibitor gefitinib when DHHC20 is inhibited these resistant cells become sensitive to gefitinib. We think this is an unprecedented approach to target cancer cell signaling.

Rotation Projects: Identification of downstream targets of Wnt5a in cancer cells and imaging of protein localization in live cells. Determine the function of polarity components during migration and invasion.

Selected Publications

Stypulkowski E, Asangani IA, and Witze ES: The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division. Science Signaling January 2018.

Sadeghi RS, Kulej K, Kathayat RS, Garcia BA, Dickinson BC, Brady DC, and Witze ES: Wnt5a Signaling Induced Phosphorylation Increases APT1 Activity and Promotes Melanoma Metastatic Behavior. eLife 7 April 2018.

Runkle KB, Kharbanda A, Stypulkowski E, Cao XJ, Wang W, Garcia BA, Witze ES: Inhibition of DHHC20-mediated EGFR palmitoylation creates a dependence on EGFR signaling. Molecular Cell 62(5): 385-96, May 2016.

Penzo-Méndez AI, Chen YJ, Li J, Witze ES, Stanger BZ: Spontaneous cell competition in immortalized mammalian cell lines. PLoS One 10(7): e0132437, July 2015.

Wang W, Snyder N, Worth AJ, Blair IA, Witze ES: Regulation of lipid synthesis by the RNA helicase Mov10 controls Wnt5a production. Oncogenesis 1(4): e154, June 2015 Notes: doi:10.1038/oncsis.2015.15.

Wang W, Runkle KB, Terkowski SM, Ekaireb RI, Witze ES: Protein depalmitoylation is induced by Wnt5a and promotes polarized cell behavior. The Journal of Biological Chemistry 290(25): 15707-16, June 2015.

Schwartz MP, Rogers RE, Singh SP, Lee JY, Loveland SG, Koepsel JT, Witze ES, Montanez-Sauri SI, Sung KE, Tokuda EY, Sharma Y, Everhart LM, Nguyen EH, Zaman MH, Beebe DJ, Ahn NG, Murphy WL, Anseth KS: A quantitative comparison of human HT-1080 fibrosarcoma cells and primary human dermal fibroblasts identifies a 3D migration mechanism with properties unique to the transformed phenotype. PLoS One 8(12): e81689, December 2013.

Londoño Gentile T, Lu C, Lodato PM, Tse S, Olejniczak SH, Witze ES, Thompson CB, Wellen KE: DNMT1 is regulated by ATP-citrate lyase and maintains methylation patterns during adipocyte differentiation. Molecular Cell Biology 33(19): 3864-78, October 2013.

Witze ES, Connacher MK, Houel S, Schwartz MP, Morphew MK, Reid L, Sacks DB, Anseth KS, Ahn NG: Wnt5a directs polarized calcium gradients by recruiting cortical endoplasmic reticulum to the cell trailing edge. Developmental Cell 26(6): 645-57, September 2013.

Witze ES, Field ED, Hunt DF, Rothman JH: C. elegans pur alpha, an activator of end-1, synergizes with the Wnt pathway to specify endoderm. Developmental Biology 327(1): 12-23, March 2009.

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Last updated: 01/15/2020
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