{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T11:01:39Z","timestamp":1784372499820,"version":"3.55.0"},"reference-count":37,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2018,4,12]],"date-time":"2018-04-12T00:00:00Z","timestamp":1523491200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,4,12]],"date-time":"2018-04-12T00:00:00Z","timestamp":1523491200000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,4,12]],"date-time":"2018-04-12T00:00:00Z","timestamp":1523491200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI118891"],"award-info":[{"award-number":["AI118891"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA181633"],"award-info":[{"award-number":["CA181633"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG-15-027-01"],"award-info":[{"award-number":["RSG-15-027-01"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["IRG \u201378-002-34"],"award-info":[{"award-number":["IRG \u201378-002-34"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.7554\/elife.34362","type":"journal-article","created":{"date-parts":[[2018,4,12]],"date-time":"2018-04-12T08:00:13Z","timestamp":1523520013000},"source":"Crossref","is-referenced-by-count":42,"title":["Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior"],"prefix":"10.7554","volume":"7","author":[{"given":"Rochelle Shirin","family":"Sadeghi","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Kulej","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9159-2413","authenticated-orcid":true,"given":"Rahul Singh","family":"Kathayat","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9616-1911","authenticated-orcid":true,"given":"Bryan C","family":"Dickinson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donita C","family":"Brady","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7699-4879","authenticated-orcid":true,"given":"Eric S","family":"Witze","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2018,4,12]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"R19","DOI":"10.1186\/bcr3614","article-title":"A novel mechanism of regulating breast cancer cell migration via palmitoylation-dependent alterations in the lipid raft affiliation of CD44","volume":"16","author":"Babina","year":"2014","journal-title":"Breast Cancer Research"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"7588","DOI":"10.1039\/C7SC02805A","article-title":"Michael addition-based probes for ratiometric fluorescence imaging of protein S-depalmitoylases in live cells and tissues","volume":"8","author":"Beck","year":"2017","journal-title":"Chemical Science"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nm.4045","article-title":"Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer","volume":"22","author":"Beltran","year":"2016","journal-title":"Nature Medicine"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1038\/35020115","article-title":"Molecular classification of cutaneous malignant melanoma by gene expression profiling","volume":"406","author":"Bittner","year":"2000","journal-title":"Nature"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/ng.3564","article-title":"Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas","volume":"48","author":"Campbell","year":"2016","journal-title":"Nature Genetics"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nature12113","article-title":"Integrated genomic characterization of endometrial carcinoma","volume":"497","author":"Cancer Genome Atlas Research Network","year":"2013","journal-title":"Nature"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/nature11404","article-title":"Comprehensive genomic characterization of squamous cell lung cancers","volume":"489","author":"Cancer Genome Atlas Research Network","year":"2012","journal-title":"Nature"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"3076","DOI":"10.1038\/sj.onc.1206448","article-title":"Gene-expression profiling in human cutaneous melanoma","volume":"22","author":"Carr","year":"2003","journal-title":"Oncogene"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discovery"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"5825","DOI":"10.1158\/1078-0432.CCR-07-5104","article-title":"WNT5A expression increases during melanoma progression and correlates with outcome","volume":"14","author":"Da Forno","year":"2008","journal-title":"Clinical Cancer Research"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1016\/S0969-2126(00)00529-3","article-title":"Crystal structure of the human acyl protein thioesterase I from a single X-ray data set to 1.5 A","volume":"8","author":"Devedjiev","year":"2000","journal-title":"Structure"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"17259","DOI":"10.1074\/jbc.M700075200","article-title":"The Wnt5A\/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition","volume":"282","author":"Dissanayake","year":"2007","journal-title":"Journal of Biological Chemistry"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/nature13952","article-title":"Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution","volume":"518","author":"Eirew","year":"2015","journal-title":"Nature"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Science Signaling"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/j.celrep.2016.03.075","article-title":"Genomic correlates of immune-cell infiltrates in colorectal carcinoma","volume":"15","author":"Giannakis","year":"2016","journal-title":"Cell Reports"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1038\/nchembio.2262","article-title":"A fluorescent probe for cysteine depalmitoylation reveals dynamic APT signaling","volume":"13","author":"Kathayat","year":"2017","journal-title":"Nature Chemical Biology"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1038\/ng.2359","article-title":"Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma","volume":"44","author":"Krauthammer","year":"2012","journal-title":"Nature Genetics"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1042\/BST20140235","article-title":"Enzymatic protein depalmitoylation by acyl protein thioesterases","volume":"43","author":"Lin","year":"2015","journal-title":"Biochemical Society Transactions"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/nrm2084","article-title":"Palmitoylation: policing protein stability and traffic","volume":"8","author":"Linder","year":"2007","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"2212","DOI":"10.1038\/nprot.2007.321","article-title":"The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability","volume":"2","author":"Niesen","year":"2007","journal-title":"Nature Protocols"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/onc.2009.305","article-title":"The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma","volume":"29","author":"O'Connell","year":"2010","journal-title":"Oncogene"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.3390\/cancers7030868","article-title":"Therapy for BRAFi-Resistant Melanomas: Is WNT5A the Answer?","volume":"7","author":"Prasad","year":"2015","journal-title":"Cancers"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1021\/acs.biochem.7b00835","article-title":"A fluorescent probe with improved water solubility permits the analysis of protein s-depalmitoylation activity in live cells","volume":"57","author":"Qiu","year":"2018","journal-title":"Biochemistry"},{"key":"bib24","first-page":"572","article-title":"Survival rates of patients with metastatic malignant melanoma","volume":"7","author":"Sandru","year":"2014","journal-title":"Journal of Medicine and Life"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/emboj.2009.322","article-title":"Wnt5a regulates distinct signalling pathways by binding to Frizzled2","volume":"29","author":"Sato","year":"2010","journal-title":"The EMBO Journal"},{"key":"bib26","first-page":"837","article-title":"Regulation of Mel-CAM\/MUC18 expression on melanocytes of different stages of tumor progression by normal keratinocytes","volume":"145","author":"Shih","year":"1994","journal-title":"The American Journal of Pathology"},{"key":"bib27","first-page":"2514","article-title":"Isolation and functional characterization of the A32 melanoma-associated antigen","volume":"54","author":"Shih","year":"1994","journal-title":"Cancer Research"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.bpj.2013.11.024","article-title":"The autodepalmitoylating activity of APT maintains the spatial organization of palmitoylated membrane proteins","volume":"106","author":"Vartak","year":"2014","journal-title":"Biophysical Journal"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1158\/0008-5472.CAN-16-2159","article-title":"Systematic in vivo inactivation of chromatin-regulating enzymes identifies setd2 as a potent tumor suppressor in lung adenocarcinoma","volume":"77","author":"Walter","year":"2017","journal-title":"Cancer Research"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1038\/nprot.2007.225","article-title":"Palmitoylated proteins: purification and identification","volume":"2","author":"Wan","year":"2007","journal-title":"Nature Protocols"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"15707","DOI":"10.1074\/jbc.M115.639609","article-title":"Protein depalmitoylation is induced by Wnt5a and promotes polarized cell behavior","volume":"290","author":"Wang","year":"2015","journal-title":"Journal of Biological Chemistry"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/S1535-6108(02)00045-4","article-title":"Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma","volume":"1","author":"Weeraratna","year":"2002","journal-title":"Cancer Cell"},{"key":"bib33","first-page":"4754","article-title":"Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression","volume":"53","author":"Wielenga","year":"1993","journal-title":"Cancer Research"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/nature01611","article-title":"Wnt proteins are lipid-modified and can act as stem cell growth factors","volume":"423","author":"Willert","year":"2003","journal-title":"Nature"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.devcel.2013.08.019","article-title":"Wnt5a directs polarized calcium gradients by recruiting cortical endoplasmic reticulum to the cell trailing edge","volume":"26","author":"Witze","year":"2013","journal-title":"Developmental Cell"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1126\/science.1151250","article-title":"Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors","volume":"320","author":"Witze","year":"2008","journal-title":"Science"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"3374","DOI":"10.1021\/acschembio.6b00720","article-title":"Molecular mechanism for isoform-selective inhibition of Acyl protein thioesterases 1 and 2 (APT1 and APT2)","volume":"11","author":"Won","year":"2016","journal-title":"ACS Chemical Biology"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/34362\/elife-34362-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/34362\/elife-34362-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/34362","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:52:39Z","timestamp":1697057559000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/34362"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,12]]},"references-count":37,"alternative-id":["10.7554\/eLife.34362"],"URL":"https:\/\/doi.org\/10.7554\/elife.34362","archive":["CLOCKSS"],"relation":{"is-supplemented-by":[{"id-type":"uri","id":"https:\/\/chorusproject.org\/pages\/dashboard.html#\/projects\/all?q=1456","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.34362.016","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.34362.017","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,12]]},"article-number":"e34362"}}