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Article ; Online: Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis.

Kadry, Yasmin A / Lee, Jia-Ying / Witze, Eric S

2021 Volume 11, Issue 10, Page(s) 210033

Abstract: The epidermal growth factor receptor (EGFR) is an essential driver of oncogenic signalling, and EGFR inhibitors are some of the earliest examples of successful targeted therapies in multiple types of cancer. The tractability of EGFR as a therapeutic ... ...

Abstract	The epidermal growth factor receptor (EGFR) is an essential driver of oncogenic signalling, and EGFR inhibitors are some of the earliest examples of successful targeted therapies in multiple types of cancer. The tractability of EGFR as a therapeutic target is overshadowed by the inevitable drug resistance that develops. Overcoming resistance mechanisms requires a deeper understanding of EGFR regulation in cancer cells. In this review, we discuss our recent discovery that the palmitoyltransferase DHHC20 palmitoylates EGFR on the C-terminal domain and plays a critical role in signal regulation during oncogenesis. Inhibiting DHHC20 expression or mutating the palmitoylation site on EGFR alters the EGF-induced signalling kinetics from a transient signal to a sustained signal. The change in signalling is accompanied by a decrease in cell proliferation in multiple human cancer cell lines. Our
MeSH term(s)	Acyltransferases/metabolism ; Adenocarcinoma of Lung/genetics ; Adenocarcinoma of Lung/metabolism ; Adenocarcinoma of Lung/pathology ; Animals ; Drug Resistance, Neoplasm ; ErbB Receptors/chemistry ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Lipoylation ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice ; Mutation ; Protein Domains ; Proto-Oncogene Proteins p21(ras)/genetics ; Signal Transduction
Chemical Substances	KRAS protein, human ; Acyltransferases (EC 2.3.-) ; ZDHHC20 protein, human (EC 2.3.-) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2021-10-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2630944-0
ISSN	2046-2441 ; 2046-2441
ISSN (online)	2046-2441
ISSN	2046-2441
DOI	10.1098/rsob.210033
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Wnt-Dependent Control of Cell Polarity in Cultured Cells.

Runkle, Kristin B / Witze, Eric S

Methods in molecular biology (Clifton, N.J.)

2016 Volume 1481, Page(s) 61–68

Abstract: The secreted ligand Wnt5a regulates cell polarity and polarized cell movement during development by signaling through the poorly defined noncanonical Wnt pathway. Cell polarity regulates most aspects of cell behavior including the organization of apical/ ... ...

Abstract	The secreted ligand Wnt5a regulates cell polarity and polarized cell movement during development by signaling through the poorly defined noncanonical Wnt pathway. Cell polarity regulates most aspects of cell behavior including the organization of apical/basolateral membrane domains of epithelial cells, polarized cell divisions along a directional plane, and front rear polarity during cell migration. These characteristics of cell polarity allow coordinated cell movements required for tissue formation and organogenesis during embryonic development. Genetic model organisms have been used to identify multiple signaling pathways including Wnt5a that are required to establish cell polarity and regulate polarized cell behavior. However, the downstream signaling events that regulate these complex cellular processes are still poorly understood. The methods below describe assays to study Wnt5a-induced cell polarity in cultured cells, which may facilitate our understanding of these complex signaling pathways.
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-6393-5_7
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Article ; Online: The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division.

Stypulkowski, Ewa / Asangani, Irfan A / Witze, Eric S

Science signaling

2018 Volume 11, Issue 511

Abstract: Asymmetric cell division results in two distinctly fated daughter cells. A molecular hallmark of asymmetric division is the unequal partitioning of cell fate determinants. We have previously established that growth factor signaling promotes protein ... ...

Abstract	Asymmetric cell division results in two distinctly fated daughter cells. A molecular hallmark of asymmetric division is the unequal partitioning of cell fate determinants. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which, in turn, drives migration and metastasis. We report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell fate determinants Numb and β-catenin through the activity of the depalmitoylating enzyme APT1. Using point mutations, we showed that specific palmitoylated residues on Numb were required for its asymmetric localization. By live-cell imaging, we showed that reciprocal interactions between APT1 and the Rho family GTPase CDC42 promoted the asymmetric localization of Numb and β-catenin to the plasma membrane. This, in turn, restricted Notch- or Wnt-responsive transcriptional activity to one daughter cell. Moreover, we showed that altering APT1 abundance changed the transcriptional signatures of MDA-MB-231 triple receptor-negative breast cancer cells, similar to changes in Notch and β-catenin-mediated Wnt signaling. We also showed that loss of APT1 depleted a specific subpopulation of tumorigenic cells in colony formation assays. Together, our findings suggest that APT1-mediated depalmitoylation is a major mechanism of asymmetric cell division that maintains Notch- and Wnt-associated protein dynamics, gene expression, and cellular functions.
MeSH term(s)	Animals ; Asymmetric Cell Division/genetics ; Cell Line, Tumor ; Cell Membrane/metabolism ; Female ; Humans ; Lipoylation ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Point Mutation ; Receptors, Notch/genetics ; Receptors, Notch/metabolism ; Thiolester Hydrolases/genetics ; Thiolester Hydrolases/metabolism ; Triple Negative Breast Neoplasms/enzymology ; Triple Negative Breast Neoplasms/genetics ; Wnt Signaling Pathway ; beta Catenin/genetics ; beta Catenin/metabolism ; cdc42 GTP-Binding Protein/genetics ; cdc42 GTP-Binding Protein/metabolism
Chemical Substances	CTNNB1 protein, human ; Membrane Proteins ; Nerve Tissue Proteins ; NUMB protein, human ; Receptors, Notch ; beta Catenin ; LYPLA1 protein, human (EC 3.1.2.-) ; Thiolester Hydrolases (EC 3.1.2.-) ; CDC42 protein, human (EC 3.6.5.2) ; cdc42 GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2018-01-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aam8705
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Article ; Online: Blocking EGFR palmitoylation suppresses PI3K signaling and mutant KRAS lung tumorigenesis.

Kharbanda, Akriti / Walter, David M / Gudiel, Andrea A / Schek, Nancy / Feldser, David M / Witze, Eric S

Science signaling

2020 Volume 13, Issue 621

Abstract: Non-small cell lung cancer (NSCLC) is often characterized by mutually exclusive mutations in the epidermal growth factor receptor (EGFR) or the guanosine triphosphatase KRAS. We hypothesized that blocking EGFR palmitoylation, previously shown to inhibit ... ...

Abstract	Non-small cell lung cancer (NSCLC) is often characterized by mutually exclusive mutations in the epidermal growth factor receptor (EGFR) or the guanosine triphosphatase KRAS. We hypothesized that blocking EGFR palmitoylation, previously shown to inhibit EGFR activity, might alter downstream signaling in the KRAS-mutant setting. Here, we found that blocking EGFR palmitoylation, by either knocking down the palmitoyltransferase DHHC20 or expressing a palmitoylation-resistant EGFR mutant, reduced activation of the kinase PI3K, the abundance of the transcription factor MYC, and the proliferation of cells in culture, as well as reduced tumor growth in a mouse model of KRAS-mutant lung adenocarcinoma. Knocking down DHHC20 reduced the growth of existing tumors derived from human KRAS-mutant lung cancer cells and increased the sensitivity of these cells to a PI3K inhibitor. Palmitoylated EGFR interacted with the PI3K regulatory subunit PIK3R1 (p85) and increased the recruitment of the PI3K heterodimer to the plasma membrane. Alternatively, blocking palmitoylation increased the association of EGFR with the MAPK adaptor Grb2 and decreased that with p85. This binary switching between MAPK and PI3K signaling, modulated by EGFR palmitoylation, was only observed in the presence of oncogenic KRAS. These findings suggest a mechanism whereby oncogenic KRAS saturates signaling through unpalmitoylated EGFR, reducing formation of the PI3K signaling complex. Future development of DHHC20 inhibitors to reduce EGFR-PI3K signaling could be beneficial to patients with KRAS-mutant tumors.
MeSH term(s)	Acyltransferases/genetics ; Acyltransferases/metabolism ; Animals ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Cell Line, Tumor ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Lipoylation ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Mice ; NIH 3T3 Cells ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Signal Transduction
Chemical Substances	KRAS protein, human ; Acyltransferases (EC 2.3.-) ; ZDHHC20 protein, human (EC 2.3.-) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2020-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aax2364
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Article ; Online: Induced sensitivity to EGFR inhibitors is mediated by palmitoylated cysteine 1025 of EGFR and requires oncogenic Kras.

Kharbanda, Akriti / Runkle, Kristin / Wang, Wei / Witze, Eric S

Biochemical and biophysical research communications

2017 Volume 493, Issue 1, Page(s) 213–219

Abstract: Currently, there are no effective therapeutic strategies targeting Kras driven cancers, and therefore, identifying new targeted therapies and overcoming drug resistance have become paramount for effective long-term cancer therapy. We have found that ... ...

Abstract	Currently, there are no effective therapeutic strategies targeting Kras driven cancers, and therefore, identifying new targeted therapies and overcoming drug resistance have become paramount for effective long-term cancer therapy. We have found that reducing expression of the palmitoyl transferase DHHC20 increases cell death induced by the EGFR inhibitor gefitinib in Kras and EGFR mutant cell lines, but not MCF7 cells harboring wildtype Kras. We show that the increased gefitinib sensitivity in cancer cells induced by DHHC20 inhibition is mediated directly through loss of palmitoylation on a previously identified cysteine residue in the C-terminal tail of EGFR. We utilized an EGFR point mutant in which the palmitoylated cysteine 1025 is mutated to alanine (EGFR
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Cocarcinogenesis ; Cysteine/genetics ; Cysteine/metabolism ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm ; Humans ; Lipoylation/drug effects ; Lipoylation/genetics ; MCF-7 Cells ; Membrane Proteins ; Mutation ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/physiopathology ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Quinazolines/administration & dosage ; Quinazolines/pharmacology ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Receptor, Epidermal Growth Factor/genetics ; Receptor, Epidermal Growth Factor/metabolism
Chemical Substances	Antineoplastic Agents ; GODZ protein, mouse ; KRAS protein, human ; Membrane Proteins ; Quinazolines ; EGFR protein, human (EC 2.7.10.1) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Cysteine (K848JZ4886) ; gefitinib (S65743JHBS)
Language	English
Publishing date	2017-09-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2017.09.044
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Article ; Online: Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior.

Sadeghi, Rochelle Shirin / Kulej, Katarzyna / Kathayat, Rahul Singh / Garcia, Benjamin A / Dickinson, Bryan C / Brady, Donita C / Witze, Eric S

eLife

2018 Volume 7

Abstract: Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood. Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated ... ...

Abstract	Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood. Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, resulting in increased melanoma invasion. The mechanistic details that underlie Wnt5a-mediated regulation of APT1 activity and cellular function remain unknown. Here, we show Wnt5a signaling regulates APT1 activity through induction of APT1 phosphorylation and we further investigate the functional role of APT1 phosphorylation on its depalmitoylating activity. We found phosphorylation increased APT1 depalmitoylating activity and reduced APT1 dimerization. We further determined APT1 phosphorylation increases melanoma invasion in vitro, and also correlated with increased tumor grade and metastasis. Our results further establish APT1 as an important regulator of melanoma invasion and metastatic behavior. Inhibition of APT1 may represent a novel way to treat Wnt5a driven cancers.
MeSH term(s)	CD146 Antigen/genetics ; CD146 Antigen/metabolism ; Cell Movement ; Cell Proliferation ; Humans ; Hyaluronan Receptors/genetics ; Hyaluronan Receptors/metabolism ; Lipoylation ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/secondary ; Neoplasm Invasiveness ; Phosphorylation ; Protein Conformation ; Protein Multimerization ; Protein Processing, Post-Translational ; Signal Transduction ; Thiolester Hydrolases/chemistry ; Thiolester Hydrolases/genetics ; Thiolester Hydrolases/metabolism ; Tumor Cells, Cultured ; Wnt-5a Protein/genetics ; Wnt-5a Protein/metabolism
Chemical Substances	CD146 Antigen ; CD44 protein, human ; Hyaluronan Receptors ; MCAM protein, human ; WNT5A protein, human ; Wnt-5a Protein ; LYPLA1 protein, human (EC 3.1.2.-) ; Thiolester Hydrolases (EC 3.1.2.-)
Language	English
Publishing date	2018-04-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.34362
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Article ; Online: Spontaneous Cell Competition in Immortalized Mammalian Cell Lines.

Penzo-Méndez, Alfredo I / Chen, Yi-Ju / Li, Jinyang / Witze, Eric S / Stanger, Ben Z

PloS one

2015 Volume 10, Issue 7, Page(s) e0132437

Abstract: Cell competition is a form of cell-cell interaction by which cells compare relative levels of fitness, resulting in the active elimination of less-fit cells, "losers," by more-fit cells, "winners." Here, we show that in three routinely-used mammalian ... ...

Abstract	Cell competition is a form of cell-cell interaction by which cells compare relative levels of fitness, resulting in the active elimination of less-fit cells, "losers," by more-fit cells, "winners." Here, we show that in three routinely-used mammalian cell lines - U2OS, 3T3, and MDCK cells - sub-clones arise stochastically that exhibit context-dependent competitive behavior. Specifically, cell death is elicited when winner and loser sub-clones are cultured together but not alone. Cell competition and elimination in these cell lines is caspase-dependent and requires cell-cell contact but does not require de novo RNA synthesis. Moreover, we show that the phenomenon involves differences in cellular metabolism. Hence, our study demonstrates that cell competition is a common feature of immortalized mammalian cells in vitro and implicates cellular metabolism as a mechanism by which cells sense relative levels of "fitness."
MeSH term(s)	3T3 Cells ; Animals ; Apoptosis ; Caspases/metabolism ; Cell Communication ; Cell Line ; Coculture Techniques/methods ; Dogs ; Humans ; Madin Darby Canine Kidney Cells ; Mice ; RNA/metabolism
Chemical Substances	RNA (63231-63-0) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0132437
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Article ; Online: Menin localization in cell membrane compartment.

He, Xin / Wang, Lei / Yan, Jizhou / Yuan, Chaoxing / Witze, Eric S / Hua, Xianxin

Cancer biology & therapy

2015 Volume 17, Issue 1, Page(s) 114–122

Abstract: Menin is encoded by the MEN1 gene, which is mutated in an inherited human syndrome, multiple endocrine neoplasia type 1(MEN1). Menin is primarily nuclear protein, acting as a tumor suppressor in endocrine organs, but as an oncogenic factor in the mixed ... ...

Abstract	Menin is encoded by the MEN1 gene, which is mutated in an inherited human syndrome, multiple endocrine neoplasia type 1(MEN1). Menin is primarily nuclear protein, acting as a tumor suppressor in endocrine organs, but as an oncogenic factor in the mixed lineage leukemia, in a tissue-specific manner. Recently, the crystal structures of menin with different binding partners reveal menin as a key scaffold protein that functionally interacts with various partners to regulate gene transcription in the nucleus. However, outside the nucleus, menin also regulates multiple signaling pathways that traverse the cell surface membrane. The precise nature regarding to how menin associates with the membrane fraction is poorly understood. Here we show that a small fraction of menin associates with the cell membrane fraction likely via serine palmitoylation. Moreover, the majority of the membrane-associated menin may reside inside membrane vesicles, as menin is protected from trypsin-mediated proteolysis, but disruption of the membrane fraction using detergent abolishes the detection. Consistently, cellular staining for menin also reveals the distribution of menin in the cell membrane and the punctate-like cell organelles. Our findings suggest that part of intracellular menin associates with the cell membrane peripherally as well as resides within the membrane vesicles.
MeSH term(s)	Animals ; Cell Membrane/genetics ; Cell Membrane/metabolism ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Crystallography, X-Ray ; Humans ; Lipoylation ; Mice ; Nuclear Matrix-Associated Proteins/chemistry ; Nuclear Matrix-Associated Proteins/genetics ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Rats ; Serine/metabolism ; Signal Transduction/genetics
Chemical Substances	MEN1 protein, human ; Nuclear Matrix-Associated Proteins ; Proto-Oncogene Proteins ; Serine (452VLY9402)
Language	English
Publishing date	2015-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2146305-0
ISSN	1555-8576 ; 1538-4047
ISSN (online)	1555-8576
ISSN	1538-4047
DOI	10.1080/15384047.2015.1108497
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Article ; Online: Protein Depalmitoylation Is Induced by Wnt5a and Promotes Polarized Cell Behavior.

Wang, Wei / Runkle, Kristin B / Terkowski, Samantha M / Ekaireb, Rachel I / Witze, Eric S

The Journal of biological chemistry

2015 Volume 290, Issue 25, Page(s) 15707–15716

Abstract: Wnt5a signaling regulates polarized cell behavior, but the downstream signaling events that promote cell polarity are not well understood. Our results show that Wnt5a promotes depalmitoylation of the melanoma cell adhesion molecule (MCAM) at cysteine 590. ...

Abstract	Wnt5a signaling regulates polarized cell behavior, but the downstream signaling events that promote cell polarity are not well understood. Our results show that Wnt5a promotes depalmitoylation of the melanoma cell adhesion molecule (MCAM) at cysteine 590. Mutation of Cys-590 to glycine is sufficient to polarize MCAM localization, similar to what is observed with Wnt5a stimulation. Inhibition of the depalmitoylating enzyme APT1 blocks Wnt5a-induced depalmitoylation, asymmetric MCAM localization, and cell invasion. Directly altering expression of the basal protein palmitoylation machinery is sufficient to promote cell invasion. Additionally, cancer mutations in palmitoyltransferases decrease MCAM palmitoylation and have impaired ability to suppress cell invasion. Our results provide evidence that Wnt5a induces protein depalmitoylation, which promotes polarized protein localization and cell invasion.
MeSH term(s)	CD146 Antigen/biosynthesis ; CD146 Antigen/genetics ; Cell Line, Tumor ; Humans ; Lipoylation ; Mutation ; Neoplasm Invasiveness ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Signal Transduction ; Thiolester Hydrolases/genetics ; Thiolester Hydrolases/metabolism ; Wnt Proteins/genetics ; Wnt Proteins/metabolism ; Wnt-5a Protein
Chemical Substances	CD146 Antigen ; MCAM protein, human ; Proto-Oncogene Proteins ; WNT5A protein, human ; Wnt Proteins ; Wnt-5a Protein ; LYPLA1 protein, human (EC 3.1.2.-) ; Thiolester Hydrolases (EC 3.1.2.-)
Language	English
Publishing date	2015-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.639609
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Article ; Online: Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling.

Runkle, Kristin B / Kharbanda, Akriti / Stypulkowski, Ewa / Cao, Xing-Jun / Wang, Wei / Garcia, Benjamin A / Witze, Eric S

Molecular cell

2016 Volume 62, Issue 3, Page(s) 385–396

Abstract: Inappropriate activation of the receptor tyrosine kinase EGFR contributes to a variety of human malignancies. Here we show a mechanism to induce vulnerability to an existing first line treatment for EGFR-driven cancers. We find that inhibiting the ... ...

Abstract	Inappropriate activation of the receptor tyrosine kinase EGFR contributes to a variety of human malignancies. Here we show a mechanism to induce vulnerability to an existing first line treatment for EGFR-driven cancers. We find that inhibiting the palmitoyltransferase DHHC20 creates a dependence on EGFR signaling for cancer cell survival. The loss of palmitoylation increases sustained EGFR signal activation and sensitizes cells to EGFR tyrosine kinase inhibition. Our work shows that the reversible modification of EGFR with palmitate "pins" the unstructured C-terminal tail to the plasma membrane, impeding EGFR activation. We identify by mass spectrometry palmitoylated cysteine residues within the C-terminal tail where mutation of the cysteine residues to alanine is sufficient to activate EGFR signaling promoting cell migration and transformation. Our results reveal that the targeting of a peripheral modulator of EGFR signaling, DHHC20, causes a loss of signal regulation and susceptibility to EGFR inhibitor-induced cell death.
MeSH term(s)	Acyltransferases/genetics ; Acyltransferases/metabolism ; Animals ; Antineoplastic Agents/pharmacology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/enzymology ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Death ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Cysteine ; Endocytosis ; Epidermal Growth Factor/pharmacology ; GRB2 Adaptor Protein/metabolism ; HEK293 Cells ; Humans ; Lipoylation ; Mass Spectrometry ; Mice ; Mutation ; NIH 3T3 Cells ; Protein Conformation ; Protein Kinase Inhibitors/pharmacology ; Protein Processing, Post-Translational ; Protein Transport ; Proteolysis ; Quinazolines/pharmacology ; RNA Interference ; Receptor, Epidermal Growth Factor/chemistry ; Receptor, Epidermal Growth Factor/drug effects ; Receptor, Epidermal Growth Factor/genetics ; Receptor, Epidermal Growth Factor/metabolism ; Signal Transduction/drug effects ; Structure-Activity Relationship ; Transfection
Chemical Substances	Antineoplastic Agents ; GRB2 Adaptor Protein ; GRB2 protein, human ; Protein Kinase Inhibitors ; Quinazolines ; Epidermal Growth Factor (62229-50-9) ; Acyltransferases (EC 2.3.-) ; ZDHHC20 protein, human (EC 2.3.-) ; EGFR protein, human (EC 2.7.10.1) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; Cysteine (K848JZ4886) ; gefitinib (S65743JHBS)
Language	English
Publishing date	2016-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2016.04.003
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