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.

doi:10.1074/jbc.m115.639609

Cited by 35 publications

(35 citation statements)

References 42 publications

(35 reference statements)

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“…The palmitoyltransferase DHHC20 is expressed in multiple human breast and lung cancer cell lines and was found to suppress metastatic behavior in melanoma cells (Figure S1) (Wang et al, 2015). Analysis of the TCGA database revealed DHHC20 mRNA is elevated in basal and HER2-enriched breast carcinoma compared to luminal A and B tumors (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling

et al. 2016

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SUMMARY 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.

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Section: Resultsmentioning

confidence: 99%

Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling

et al. 2016

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“…Non-canonical WNT/PCP signaling through FZD receptors and Dishevelled (DVL) adaptor proteins regulates the coordinated cellular orientation within an epithelial plane, collective cell movements during gastrulation and neurulation stages of embryogenesis and directional cell movement during invasion and metastasis of cancer cells ( 58 – 62 ). WNT/PCP signals are converted to actin cytoskeletal dynamics via the small G-proteins RAC and RHO ( Fig.…”

Section: Non-canonical Wnt Signaling In Cscs and Their Nichesmentioning

confidence: 99%

Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

Katoh

2017

International Journal of Oncology

362

338

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Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49). Aberrant canonical and non-canonical WNT signaling in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate and uterine cancers, leukemia and melanoma, are involved in CSC survival, bulk-tumor expansion and invasion/metastasis. WNT signaling-targeted therapeutics, such as anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 mAb (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 and WNT974), tankyrase inhibitors (AZ1366, G007-LK, NVP-TNKS656 and XAV939) and β-catenin inhibitors (BC2059, CWP232228, ICG-001 and PRI-724), are in clinical trials or preclinical studies for the treatment of patients with WNT-driven cancers. WNT signaling-targeted therapeutics are applicable for combination therapy with BCR-ABL, EGFR, FLT3, KIT or RET inhibitors to treat a subset of tyrosine kinase-driven cancers because WNT and tyrosine kinase signaling cascades converge to β-catenin for the maintenance and expansion of CSCs. WNT signaling-targeted therapeutics might also be applicable for combination therapy with immune checkpoint blockers, such as atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab, to treat cancers with immune evasion, although the context-dependent effects of WNT signaling on immunity should be carefully assessed. Omics monitoring, such as genome sequencing and transcriptome tests, immunohistochemical analyses on PD-L1 (CD274), PD-1 (PDCD1), ROR1 and nuclear β-catenin and organoid-based drug screening, is necessary to determine the appropriate WNT signaling-targeted therapeutics for cancer patients.

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“…Cell migration in turn was shown to depend on the Sacylation of the adhesion protein CD44 (Babina et al 2014). Interestingly, non-canonical Wnt signaling was reported to induce APT1-dependent S-deacylation of CD44 and melanoma cell adhesion molecule (MCAM) in melanoma cells thus promoting polarized protein localization and cell invasion (Wang et al 2015).…”

Section: Cell Polarity and Migrationmentioning

confidence: 99%

The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics

Zaballa

Goot

2018

Critical Reviews in Biochemistry and Molecular Biology

102

129

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S-Acylation (commonly referred to as S-palmitoylation) is a post-translational modification consisting in the covalent attachment of an acyl chain to a cysteine residue of the target protein. The lability of the resulting thioester bond gives S-acylation an essential characteristic: its reversibility. S-acylation dynamically regulates different aspects in the life of a protein (including stability, localization, interactome, and function) and, thus, plays critical roles in cellular physiology. For long, the reversibility of S-acylation has been neglected and thereby its potential as a regulatory mechanism for protein function undervalued. Thanks to technological advances, the field has now entered its golden era. A great diversity of interesting targets is being identified, the physio-pathological importance of the modification is starting to be revealed, structural information on the enzymes is becoming available, and the regulatory dynamics are gradually being understood. Here we will review the most recent literature in the S-acylation field, with a special focus on the molecular aspects of the modification, its regulation, and its consequences.

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Protein Depalmitoylation Is Induced by Wnt5a and Promotes Polarized Cell Behavior

Cited by 35 publications

References 42 publications

Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling

Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling

Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics

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