{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T14:45:02Z","timestamp":1790261102159,"version":"4.1.0"},"reference-count":88,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T00:00:00Z","timestamp":1670198400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T00:00:00Z","timestamp":1670198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100017067","name":"Sbarro Health Research Organization","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017067","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Exp Clin Cancer Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Mesothelioma is an aggressive disease with limited therapeutic options. The growth factor progranulin plays a critical role in several cancer models, where it regulates tumor initiation and progression. Recent data from our laboratories have demonstrated that progranulin and its receptor, EphA2, constitute an oncogenic pathway in bladder cancer by promoting motility, invasion and <jats:italic>in vivo<\/jats:italic> tumor formation. Progranulin and EphA2 are expressed in mesothelioma cells but their mechanisms of action are not well defined. In addition, there are no data establishing whether the progranulin\/EphA2 axis is tumorigenic for mesothelioma cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The expression of progranulin in various mesothelioma cell lines derived from all major mesothelioma subtypes was examined by western blots on cell lysates, conditioned media and ELISA assays. The biological roles of progranulin, EphA2, EGFR, RYK and FAK were assessed <jats:italic>in vitro<\/jats:italic> by immunoblots, human phospho-RTK antibody arrays, pharmacological (specific inhibitors) and genetic (siRNAs, shRNAs, CRISPR\/Cas9) approaches, motility, invasion and adhesion assays. <jats:italic>In vivo<\/jats:italic> tumorigenesis was determined by xenograft models. Focal adhesion turnover was evaluated biochemically using focal adhesion assembly\/disassembly assays and immunofluorescence analysis with focal adhesion-specific markers.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In the present study we show that progranulin is upregulated in various mesothelioma cell lines covering all mesothelioma subtypes and is an important regulator of motility, invasion, adhesion and <jats:italic>in vivo<\/jats:italic> tumor formation. However, our results indicate that EphA2 is not the major functional receptor for progranulin in mesothelioma cells, where progranulin activates a complex signaling network including EGFR and RYK. We further characterized progranulin mechanisms of action and demonstrated that progranulin, by modulating FAK activity, regulates the kinetic of focal adhesion disassembly, a critical step for cell motility.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Collectively, our results highlight the complexity of progranulin oncogenic signaling in mesothelioma, where progranulin modulate functional cross-talks between multiple RTKs, thereby suggesting the need for combinatorial therapeutic approaches to improve treatments of this aggressive disease.\n<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13046-022-02546-4","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T05:05:37Z","timestamp":1670216737000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Complexity of progranulin mechanisms of action in mesothelioma"],"prefix":"10.1186","volume":"41","author":[{"given":"Elisa","family":"Ventura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Buraschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Belfiore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato V.","family":"Iozzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Giordano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2319-7884","authenticated-orcid":false,"given":"Andrea","family":"Morrione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,5]]},"reference":[{"issue":"1","key":"2546_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","volume":"71","author":"RL Siegel","year":"2021","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7\u201333.","journal-title":"CA Cancer J Clin."},{"key":"2546_CR2","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.lungcan.2018.11.034","volume":"127","author":"L Wu","year":"2019","unstructured":"Wu L, Dell\u2019Anno I, Lapidot M, Sekido Y, Chan ML, Kohno M, et al. Progress of malignant mesothelioma research in basic science: A review of the 14th international conference of the international mesothelioma interest group (iMig2018). Lung Cancer. 2019;127:138\u201345.","journal-title":"Lung Cancer"},{"issue":"5","key":"2546_CR3","doi-asserted-by":"publisher","first-page":"402","DOI":"10.3322\/caac.21572","volume":"69","author":"M Carbone","year":"2019","unstructured":"Carbone M, Adusumilli PS, Alexander HR Jr, Baas P, Bardelli F, Bononi A, et al. Mesothelioma: Scientific clues for prevention, diagnosis, and therapy. CA Cancer J Clin. 2019;69(5):402\u201329.","journal-title":"CA Cancer J Clin"},{"issue":"7","key":"2546_CR4","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.jtho.2022.03.014","volume":"17","author":"M Carbone","year":"2022","unstructured":"Carbone M, Pass HI, Ak G, Alexander HR Jr, Baas P, Baumann F, et al. Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations. J Thorac Oncol. 2022;17(7):873\u201389.","journal-title":"J Thorac Oncol"},{"issue":"1","key":"2546_CR5","doi-asserted-by":"publisher","first-page":"1819","DOI":"10.1038\/s41467-021-22142-y","volume":"12","author":"MG Zauderer","year":"2021","unstructured":"Zauderer MG. The therapeutic implications of the genomic analysis of malignant pleural mesothelioma. Nat Commun. 2021;12(1):1819.","journal-title":"Nat Commun"},{"issue":"3","key":"2546_CR6","doi-asserted-by":"publisher","first-page":"924","DOI":"10.21037\/tlcr.2020.03.38","volume":"9","author":"L Brcic","year":"2020","unstructured":"Brcic L, Kern I. Clinical significance of histologic subtyping of malignant pleural mesothelioma. Translational Lung Cancer Research. 2020;9(3):924\u201333.","journal-title":"Translational Lung Cancer Research"},{"key":"2546_CR7","doi-asserted-by":"publisher","first-page":"e2100422","DOI":"10.1200\/PO.21.00422","volume":"6","author":"I Dagogo-Jack","year":"2022","unstructured":"Dagogo-Jack I, Madison RW, Lennerz JK, Chen KT, Hopkins JF, Schrock AB, et al. Molecular Characterization of Mesothelioma: Impact of Histologic Type and Site of Origin on Molecular Landscape. JCO Precis Oncol. 2022;6:e2100422.","journal-title":"JCO Precis Oncol"},{"issue":"39","key":"2546_CR8","doi-asserted-by":"publisher","first-page":"32298","DOI":"10.1074\/jbc.R112.399170","volume":"287","author":"B Cenik","year":"2012","unstructured":"Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G. Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration. J Biol Chem. 2012;287(39):32298\u2013306.","journal-title":"J Biol Chem"},{"issue":"5","key":"2546_CR9","doi-asserted-by":"publisher","first-page":"2214","DOI":"10.1111\/ejn.13297","volume":"44","author":"S Rollinson","year":"2016","unstructured":"Rollinson S, Young K, Bennion-Callister J, Pickering-Brown SM. Identification of biological pathways regulated by PGRN and GRN peptide treatments using transcriptome analysis. Eur J Neurosci. 2016;44(5):2214\u201325.","journal-title":"Eur J Neurosci"},{"issue":"3","key":"2546_CR10","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1007\/s12031-011-9625-0","volume":"45","author":"S Kumar-Singh","year":"2011","unstructured":"Kumar-Singh S. Progranulin and TDP-43: mechanistic links and future directions. J Mol Neurosci. 2011;45(3):561\u201373.","journal-title":"J Mol Neurosci"},{"issue":"10","key":"2546_CR11","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1007\/s00109-003-0474-3","volume":"81","author":"Z He","year":"2003","unstructured":"He Z, Bateman A. Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med. 2003;81(10):600\u201312.","journal-title":"J Mol Med"},{"issue":"2","key":"2546_CR12","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1677\/joe.0.1580145","volume":"158","author":"A Bateman","year":"1998","unstructured":"Bateman A, Bennett HP. Granulins: the structure and function of an emerging family of growth factors. J Endocrinol. 1998;158(2):145\u201351.","journal-title":"J Endocrinol"},{"issue":"12","key":"2546_CR13","doi-asserted-by":"publisher","first-page":"3081","DOI":"10.1093\/brain\/awx198","volume":"140","author":"BP Chitramuthu","year":"2017","unstructured":"Chitramuthu BP, Bennett HPJ, Bateman A. Progranulin: a new avenue towards the understanding and treatment of neurodegenerative disease. Brain. 2017;140(12):3081\u2013104.","journal-title":"Brain"},{"issue":"3","key":"2546_CR14","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.2353\/ajpath.2009.080735","volume":"174","author":"G Monami","year":"2009","unstructured":"Monami G, Emiliozzi V, Bitto A, Lovat F, Xu SQ, Goldoni S, et al. Proepithelin regulates prostate cancer cell biology by promoting cell growth, migration, and anchorage-independent growth. Am J Pathol. 2009;174(3):1037\u201347.","journal-title":"Am J Pathol"},{"key":"2546_CR15","doi-asserted-by":"publisher","first-page":"100","DOI":"10.3389\/fendo.2016.00100","volume":"7","author":"R Tanimoto","year":"2016","unstructured":"Tanimoto R, Lu KG, Xu SQ, Buraschi S, Belfiore A, Iozzo RV, et al. Mechanisms of Progranulin Action and Regulation in Genitourinary Cancers. Front Endocrinol (Lausanne). 2016;7:100.","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"1","key":"2546_CR16","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1210\/en.2014-1590","volume":"156","author":"R Tanimoto","year":"2015","unstructured":"Tanimoto R, Morcavallo A, Terracciano M, Xu SQ, Stefanello M, Buraschi S, et al. Sortilin regulates progranulin action in castration-resistant prostate cancer cells. Endocrinology. 2015;156(1):58\u201370.","journal-title":"Endocrinology"},{"key":"2546_CR17","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.matbio.2017.04.001","volume":"64","author":"R Tanimoto","year":"2017","unstructured":"Tanimoto R, Palladino C, Xu SQ, Buraschi S, Neill T, Gomella LG, et al. The perlecan-interacting growth factor progranulin regulates ubiquitination, sorting, and lysosomal degradation of sortilin. Matrix Biol. 2017;64:27\u201339.","journal-title":"Matrix Biol"},{"issue":"14","key":"2546_CR18","doi-asserted-by":"publisher","first-page":"7103","DOI":"10.1158\/0008-5472.CAN-06-0633","volume":"66","author":"G Monami","year":"2006","unstructured":"Monami G, Gonzalez EM, Hellman M, Gomella LG, Baffa R, Iozzo RV, et al. Proepithelin promotes migration and invasion of 5637 bladder cancer cells through the activation of ERK1\/2 and the formation of a paxillin\/FAK\/ERK complex. Cancer Res. 2006;66(14):7103\u201310.","journal-title":"Cancer Res"},{"issue":"5","key":"2546_CR19","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1093\/carcin\/bgp050","volume":"30","author":"F Lovat","year":"2009","unstructured":"Lovat F, Bitto A, Xu SQ, Fassan M, Goldoni S, Metalli D, et al. Proepithelin is an autocrine growth factor for bladder cancer. Carcinogenesis. 2009;30(5):861\u20138.","journal-title":"Carcinogenesis"},{"issue":"13","key":"2546_CR20","doi-asserted-by":"publisher","first-page":"10825","DOI":"10.18632\/oncotarget.3424","volume":"6","author":"SQ Xu","year":"2015","unstructured":"Xu SQ, Buraschi S, Morcavallo A, Genua M, Shirao T, Peiper SC, et al. A novel role for drebrin in regulating progranulin bioactivity in bladder cancer. Oncotarget. 2015;6(13):10825\u201339.","journal-title":"Oncotarget"},{"key":"2546_CR21","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/978-1-4939-8559-3_9","volume":"1806","author":"S Xu","year":"2018","unstructured":"Xu S, Buraschi S, Tanimoto R, Stefanello M, Belfiore A, Iozzo RV, et al. Analysis of Progranulin-Mediated Akt and MAPK Activation. Methods Mol Biol. 2018;1806:121\u201330.","journal-title":"Methods Mol Biol"},{"issue":"26","key":"2546_CR22","doi-asserted-by":"publisher","first-page":"39980","DOI":"10.18632\/oncotarget.9556","volume":"7","author":"S Buraschi","year":"2016","unstructured":"Buraschi S, Xu SQ, Stefanello M, Moskalev I, Morcavallo A, Genua M, et al. Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin. Oncotarget. 2016;7(26):39980\u201395.","journal-title":"Oncotarget"},{"issue":"5","key":"2546_CR23","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1083\/jcb.201603079","volume":"215","author":"T Neill","year":"2016","unstructured":"Neill T, Buraschi S, Goyal A, Sharpe C, Natkanski E, Schaefer L, et al. EphA2 is a functional receptor for the growth factor progranulin. J Cell Biol. 2016;215(5):687\u2013703.","journal-title":"J Cell Biol"},{"key":"2546_CR24","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.matbio.2020.03.009","volume":"93","author":"S Buraschi","year":"2020","unstructured":"Buraschi S, Neill T, Xu SQ, Palladino C, Belfiore A, Iozzo RV, et al. Progranulin\/EphA2 axis: A novel oncogenic mechanism in bladder cancer. Matrix Biol. 2020;93:10\u201324.","journal-title":"Matrix Biol"},{"key":"2546_CR25","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nrm856","volume":"3","author":"K Kullander","year":"2002","unstructured":"Kullander K, Klein R. Mechanisms and functions of Eph and ephrin signaling. Nat Rev Mol Cell Biol. 2002;3:475\u201386.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"6","key":"2546_CR26","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1038\/nrm1662","volume":"6","author":"EB Pasquale","year":"2005","unstructured":"Pasquale EB. Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol. 2005;6(6):462\u201375.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"1","key":"2546_CR27","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.cell.2008.03.011","volume":"133","author":"EB Pasquale","year":"2008","unstructured":"Pasquale EB. Eph-ephrin bidirectional signaling in physiology and disease. Cell. 2008;133(1):38\u201352.","journal-title":"Cell"},{"issue":"4","key":"2546_CR28","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/j.jid.2020.08.012","volume":"141","author":"C Zhang","year":"2021","unstructured":"Zhang C, Smalley I, Emmons MF, Sharma R, Izumi V, Messina J, et al. Noncanonical EphA2 Signaling Is a Driver of Tumor-Endothelial Cell Interactions and Metastatic Dissemination in BRAF Inhibitor-Resistant Melanoma. J Invest Dermatol. 2021;141(4):840-51.e4.","journal-title":"J Invest Dermatol"},{"key":"2546_CR29","doi-asserted-by":"publisher","first-page":"7679","DOI":"10.1038\/ncomms8679","volume":"6","author":"Y Zhou","year":"2015","unstructured":"Zhou Y, Yamada N, Tanaka T, Hori T, Yokoyama S, Hayakawa Y, et al. Crucial roles of RSK in cell motility by catalysing serine phosphorylation of EphA2. Nat Commun. 2015;6:7679.","journal-title":"Nat Commun"},{"key":"2546_CR30","doi-asserted-by":"crossref","unstructured":"Eguchi R, Nakano T, Wakabayashi I. Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells. Oncogene. 2017;(36):714\u2013722.","DOI":"10.1038\/onc.2016.226"},{"issue":"9","key":"2546_CR31","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/s41389-019-0159-6","volume":"8","author":"YC Tan","year":"2019","unstructured":"Tan YC, Srivastava S, Won BM, Kanteti R, Arif Q, Husain AN, et al. EPHA2 mutations with oncogenic characteristics in squamous cell lung cancer and malignant pleural mesothelioma. Oncogenesis. 2019;8(9):49.","journal-title":"Oncogenesis"},{"issue":"2","key":"2546_CR32","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.canlet.2007.09.005","volume":"258","author":"N Nasreen","year":"2007","unstructured":"Nasreen N, Mohammed KA, Lai Y, Antony VB. Receptor EphA2 activation with ephrinA1 suppresses growth of malignant mesothelioma (MM). Cancer Lett. 2007;258(2):215\u201322.","journal-title":"Cancer Lett"},{"issue":"10","key":"2546_CR33","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1002\/cncr.22254","volume":"107","author":"N Nasreen","year":"2006","unstructured":"Nasreen N, Mohammed KA, Antony VB. Silencing the receptor EphA2 suppresses the growth and haptotaxis of malignant mesothelioma cells. Cancer. 2006;107(10):2425\u201335.","journal-title":"Cancer"},{"issue":"40","key":"2546_CR34","doi-asserted-by":"publisher","first-page":"38113","DOI":"10.1074\/jbc.C300310200","volume":"278","author":"EM Gonzalez","year":"2003","unstructured":"Gonzalez EM, Mongiat M, Slater SJ, Baffa R, Iozzo RV. A novel interaction between perlecan protein core and progranulin: potential effects on tumor growth. J Biol Chem. 2003;278(40):38113\u20136.","journal-title":"J Biol Chem"},{"issue":"19","key":"2546_CR35","doi-asserted-by":"publisher","first-page":"5025","DOI":"10.3390\/cancers13195025","volume":"13","author":"E Ventura","year":"2021","unstructured":"Ventura E, Iannuzzi CA, Pentimalli F, Giordano A, Morrione A. RBL1\/p107 expression levels are modulated by multiple signaling pathways. Cancers (Basel). 2021;13(19):5025. https:\/\/doi.org\/10.3390\/cancers13195025.","journal-title":"Cancers (Basel)."},{"issue":"5","key":"2546_CR36","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/j.cell.2017.01.013","volume":"168","author":"T Wang","year":"2017","unstructured":"Wang T, Yu H, Hughes NW, Liu B, Kendirli A, Klein K, et al. Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras. Cell. 2017;168(5):890-903.e15.","journal-title":"Cell"},{"issue":"35","key":"2546_CR37","doi-asserted-by":"publisher","first-page":"4842","DOI":"10.1038\/sj.onc.1204649","volume":"20","author":"A Morrione","year":"2001","unstructured":"Morrione A, Navarro M, Romano G, Dews M, Reiss K, Valentinis B, et al. The role of the insulin receptor substrate-1 in the differentiation of rat hippocampal neuronal cells. Oncogene. 2001;20(35):4842\u201352.","journal-title":"Oncogene"},{"issue":"8","key":"2546_CR38","first-page":"2263","volume":"60","author":"A Morrione","year":"2000","unstructured":"Morrione A, Romano G, Navarro M, Reiss K, Valentinis B, Dews M, et al. Insulin-like growth factor I receptor signaling in differentiation of neuronal H19\u20137 cells. Cancer Res. 2000;60(8):2263\u201372.","journal-title":"Cancer Res"},{"issue":"4","key":"2546_CR39","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402\u20138.","journal-title":"Methods"},{"key":"2546_CR40","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.ceb.2017.01.003","volume":"45","author":"EG Kleinschmidt","year":"2017","unstructured":"Kleinschmidt EG, Schlaepfer DD. Focal adhesion kinase signaling in unexpected places. Curr Opin Cell Biol. 2017;45:24\u201330.","journal-title":"Curr Opin Cell Biol"},{"issue":"5","key":"2546_CR41","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/35010517","volume":"2","author":"DJ Sieg","year":"2000","unstructured":"Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, et al. FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol. 2000;2(5):249\u201356.","journal-title":"Nat Cell Biol"},{"key":"2546_CR42","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.775391","volume":"15","author":"BP Chitramuthu","year":"2021","unstructured":"Chitramuthu BP, Campos-Garc\u00eda VR, Bateman A. Multiple Molecular Pathways Are Influenced by Progranulin in a Neuronal Cell Model-A Parallel Omics Approach. Front Neurosci. 2021;15: 775391.","journal-title":"Front Neurosci"},{"issue":"2","key":"2546_CR43","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.devcel.2010.01.013","volume":"18","author":"A Tomar","year":"2010","unstructured":"Tomar A, Schlaepfer DD. A PAK-activated linker for EGFR and FAK. Dev Cell. 2010;18(2):170\u20132.","journal-title":"Dev Cell"},{"issue":"3","key":"2546_CR44","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.molcel.2010.01.004","volume":"37","author":"W Long","year":"2010","unstructured":"Long W, Yi P, Amazit L, LaMarca HL, Ashcroft F, Kumar R, et al. SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration. Mol Cell. 2010;37(3):321\u201332.","journal-title":"Mol Cell"},{"issue":"23","key":"2546_CR45","doi-asserted-by":"publisher","first-page":"9107","DOI":"10.3390\/ijms21239107","volume":"21","author":"J W\u00f6rthm\u00fcller","year":"2020","unstructured":"W\u00f6rthm\u00fcller J, R\u00fcegg C. The crosstalk between FAK and Wnt signaling pathways in cancer and its therapeutic implication. Int J Mol Sci. 2020;21(23):9107. https:\/\/doi.org\/10.3390\/ijms21239107.","journal-title":"Int J Mol Sci."},{"key":"2546_CR46","doi-asserted-by":"publisher","unstructured":"Gao C, Chen G, Kuan SF, Zhang DH, Schlaepfer DD, Hu J. FAK\/PYK2 promotes the Wnt\/\u03b2-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3\u03b2. Elife. 2015;4:e10072. https:\/\/doi.org\/10.7554\/eLife.10072.","DOI":"10.7554\/eLife.10072"},{"issue":"4","key":"2546_CR47","doi-asserted-by":"publisher","first-page":"E97","DOI":"10.1038\/ncb0402-e97","volume":"4","author":"DJ Webb","year":"2002","unstructured":"Webb DJ, Parsons JT, Horwitz AF. Adhesion assembly, disassembly and turnover in migrating cells \u2013 over and over and over again. Nat Cell Biol. 2002;4(4):E97-100.","journal-title":"Nat Cell Biol"},{"issue":"12","key":"2546_CR48","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1038\/nrm971","volume":"3","author":"JV Small","year":"2002","unstructured":"Small JV, Geiger B, Kaverina I, Bershadsky A. How do microtubules guide migrating cells? Nat Rev Mol Cell Biol. 2002;3(12):957\u201364.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2546_CR49","doi-asserted-by":"publisher","unstructured":"Seetharaman S, Etienne-Manneville S. Microtubules at focal adhesions - a double-edged sword. J Cell Sci. 2019;132(19):jcs232843. https:\/\/doi.org\/10.1242\/jcs.232843.","DOI":"10.1242\/jcs.232843"},{"issue":"6","key":"2546_CR50","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/ncb1262","volume":"7","author":"EJ Ezratty","year":"2005","unstructured":"Ezratty EJ, Partridge MA, Gundersen GG. Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase. Nat Cell Biol. 2005;7(6):581\u201390.","journal-title":"Nat Cell Biol"},{"issue":"4","key":"2546_CR51","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/sj.bjc.6604901","volume":"100","author":"Y Xu","year":"2009","unstructured":"Xu Y, Benlimame N, Su J, He Q, Alaoui-Jamali MA. Regulation of focal adhesion turnover by ErbB signalling in invasive breast cancer cells. Br J Cancer. 2009;100(4):633\u201343.","journal-title":"Br J Cancer"},{"key":"2546_CR52","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-1-4939-8559-3_1","volume":"1806","author":"A Bateman","year":"2018","unstructured":"Bateman A, Cheung ST, Bennett HPJ. A Brief Overview of Progranulin in Health and Disease. Methods Mol Biol. 2018;1806:3\u201315.","journal-title":"Methods Mol Biol"},{"key":"2546_CR53","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1007\/978-3-030-73119-9_22","volume":"1329","author":"G Serrero","year":"2021","unstructured":"Serrero G. Progranulin\/GP88, A Complex and Multifaceted Player of Tumor Growth by Direct Action and via the Tumor Microenvironment. Adv Exp Med Biol. 2021;1329:475\u201398.","journal-title":"Adv Exp Med Biol"},{"issue":"5","key":"2546_CR54","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1083\/jcb.201610097","volume":"215","author":"B Chitramuthu","year":"2016","unstructured":"Chitramuthu B, Bateman A. Progranulin and the receptor tyrosine kinase EphA2, partners in crime? J Cell Biol. 2016;215(5):603\u20135.","journal-title":"J Cell Biol"},{"key":"2546_CR55","doi-asserted-by":"crossref","unstructured":"Holler CJ, Taylor G, Deng Q, Kukar T. Intracellular proteolysis of progranulin generates stable, lysosomal granulins that are haploinsufficient in patients with frontotemporal dementia caused by GRN mutations. eNeuro. 2017;4(4).","DOI":"10.1523\/ENEURO.0100-17.2017"},{"key":"2546_CR56","doi-asserted-by":"crossref","unstructured":"Simon MJ, Logan T, DeVos SL, Di Paolo G. Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia. Trends Cell Biol. 2022.","DOI":"10.1016\/j.tcb.2022.09.006"},{"issue":"23","key":"2546_CR57","doi-asserted-by":"publisher","first-page":"3929","DOI":"10.1038\/s41388-021-01798-2","volume":"40","author":"Q Xu","year":"2021","unstructured":"Xu Q, Zhang J, Telfer BA, Zhang H, Ali N, Chen F, et al. The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion. Oncogene. 2021;40(23):3929\u201341.","journal-title":"Oncogene"},{"issue":"5","key":"2546_CR58","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1083\/jcb.201107021","volume":"194","author":"JD Berndt","year":"2011","unstructured":"Berndt JD, Aoyagi A, Yang P, Anastas JN, Tang L, Moon RT. Mindbomb 1, an E3 ubiquitin ligase, forms a complex with RYK to activate Wnt\/\u03b2-catenin signaling. J Cell Biol. 2011;194(5):737\u201350.","journal-title":"J Cell Biol"},{"issue":"1\u20132","key":"2546_CR59","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1080\/08977194.2018.1472089","volume":"36","author":"JP Roy","year":"2018","unstructured":"Roy JP, Halford MM, Stacker SA. The biochemistry, signalling and disease relevance of RYK and other WNT-binding receptor tyrosine kinases. Growth Factors. 2018;36(1\u20132):15\u201340.","journal-title":"Growth Factors"},{"key":"2546_CR60","doi-asserted-by":"publisher","first-page":"555245","DOI":"10.3389\/fimmu.2020.555245","volume":"11","author":"A Rodriguez-Trillo","year":"2020","unstructured":"Rodriguez-Trillo A, Mosquera N, Pena C, Rivas-Tob\u00edo F, Mera-Varela A, Gonzalez A, et al. Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes. Front Immunol. 2020;11:555245.","journal-title":"Front Immunol"},{"issue":"3","key":"2546_CR61","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1016\/j.molcel.2020.06.018","volume":"79","author":"JB Sheetz","year":"2020","unstructured":"Sheetz JB, Mathea S, Karvonen H, Malhotra K, Chatterjee D, Niininen W, et al. Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases. Mol Cell. 2020;79(3):390-405.e7.","journal-title":"Mol Cell"},{"issue":"13","key":"2546_CR62","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1242\/dev.017319","volume":"135","author":"RR Wouda","year":"2008","unstructured":"Wouda RR, Bansraj MR, de Jong AW, Noordermeer JN, Fradkin LG. Src family kinases are required for WNT5 signaling through the Derailed\/RYK receptor in the Drosophila embryonic central nervous system. Development. 2008;135(13):2277\u201387.","journal-title":"Development"},{"issue":"2","key":"2546_CR63","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1139\/O10-145","volume":"89","author":"L Truitt","year":"2011","unstructured":"Truitt L, Freywald A. Dancing with the dead: Eph receptors and their kinase-null partners. Biochem Cell Biol. 2011;89(2):115\u201329.","journal-title":"Biochem Cell Biol"},{"issue":"2","key":"2546_CR64","doi-asserted-by":"publisher","first-page":"G352","DOI":"10.1152\/ajpgi.00228.2019","volume":"318","author":"Y Fu","year":"2020","unstructured":"Fu Y, Chen Y, Huang J, Cai Z, Wang Y. RYK, a receptor of noncanonical Wnt ligand Wnt5a, is positively correlated with gastric cancer tumorigenesis and potential of liver metastasis. Am J Physiol Gastrointest Liver Physiol. 2020;318(2):G352\u201360.","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"8","key":"2546_CR65","doi-asserted-by":"publisher","first-page":"13476","DOI":"10.18632\/oncotarget.14564","volume":"8","author":"A Adamo","year":"2017","unstructured":"Adamo A, Fiore D, De Martino F, Roscigno G, Affinito A, Donnarumma E, et al. RYK promotes the stemness of glioblastoma cells via the WNT\/ \u03b2-catenin pathway. Oncotarget. 2017;8(8):13476\u201387.","journal-title":"Oncotarget"},{"issue":"1","key":"2546_CR66","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1093\/jb\/mvu015","volume":"156","author":"M Habu","year":"2014","unstructured":"Habu M, Koyama H, Kishida M, Kamino M, Iijima M, Fuchigami T, et al. Ryk is essential for Wnt-5a-dependent invasiveness in human glioma. J Biochem. 2014;156(1):29\u201338.","journal-title":"J Biochem"},{"issue":"43","key":"2546_CR67","doi-asserted-by":"publisher","first-page":"27293","DOI":"10.18632\/oncotarget.25551","volume":"9","author":"S Thiele","year":"2018","unstructured":"Thiele S, Zimmer A, G\u00f6bel A, Rachner TD, Rother S, Fuessel S, et al. Role of WNT5A receptors FZD5 and RYK in prostate cancer cells. Oncotarget. 2018;9(43):27293\u2013304.","journal-title":"Oncotarget"},{"key":"2546_CR68","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.lungcan.2021.02.017","volume":"154","author":"S Ohara","year":"2021","unstructured":"Ohara S, Suda K, Fujino T, Hamada A, Koga T, Nishino M, et al. Dose-dependence in acquisition of drug tolerant phenotype and high RYK expression as a mechanism of osimertinib tolerance in lung cancer. Lung Cancer. 2021;154:84\u201391.","journal-title":"Lung Cancer"},{"key":"2546_CR69","doi-asserted-by":"crossref","unstructured":"W\u00f6rthm\u00fcller J, Salicio V, Oberson A, Blum W, Schwaller B. Modulation of calretinin expression in human mesothelioma cells reveals the implication of the FAK and Wnt signaling pathways in conferring chemoresistance towards cisplatin. Int J Mol Sci. 2019;20(21).","DOI":"10.3390\/ijms20215391"},{"issue":"9","key":"2546_CR70","doi-asserted-by":"publisher","first-page":"7391","DOI":"10.1002\/jcp.26579","volume":"233","author":"M Barbarino","year":"2018","unstructured":"Barbarino M, Cesari D, Intruglio R, Indovina P, Namagerdi A, Bertolino FM, et al. Possible repurposing of pyrvinium pamoate for the treatment of mesothelioma: A pre-clinical assessment. J Cell Physiol. 2018;233(9):7391\u2013401.","journal-title":"J Cell Physiol"},{"issue":"1","key":"2546_CR71","doi-asserted-by":"publisher","first-page":"362","DOI":"10.3892\/ijo.2017.4011","volume":"51","author":"V Perumal","year":"2017","unstructured":"Perumal V, Dharmarajan AM, Fox SA. The Wnt regulator SFRP4 inhibits mesothelioma cell proliferation, migration, and antagonizes Wnt3a via its netrin-like domain. Int J Oncol. 2017;51(1):362\u20138.","journal-title":"Int J Oncol"},{"key":"2546_CR72","doi-asserted-by":"crossref","unstructured":"Belfiore A, Busico A, Bozzi F, Brich S, Dallera E, Conca E, et al. Molecular signatures for combined targeted treatments in diffuse malignant peritoneal mesothelioma. Int J Mol Sci. 2019;20(22).","DOI":"10.3390\/ijms20225817"},{"issue":"4","key":"2546_CR73","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1503\/jpn.150131","volume":"41","author":"C Alqu\u00e9zar","year":"2016","unstructured":"Alqu\u00e9zar C, de la Encarnaci\u00f3n A, Moreno F, Mart\u00edn-Requero \u00c1, Mart\u00edn-Requero \u00c1. Progranulin deficiency induces overactivation of WNT5A expression via TNF-\u03b1\/NF-\u03baB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers. J Psychiatry Neurosci. 2016;41(4):225\u201339.","journal-title":"J Psychiatry Neurosci."},{"issue":"4","key":"2546_CR74","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1016\/j.neurobiolaging.2013.09.021","volume":"35","author":"C Alqu\u00e9zar","year":"2014","unstructured":"Alqu\u00e9zar C, Esteras N, de la Encarnaci\u00f3n A, Alzualde A, Moreno F, et al. PGRN haploinsufficiency increased Wnt5a signaling in peripheral cells from frontotemporal lobar degeneration-progranulin mutation carriers. Neurobiol Aging. 2014;35(4):886\u201398.","journal-title":"Neurobiol Aging."},{"issue":"6","key":"2546_CR75","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1053\/j.seminoncol.2015.09.020","volume":"42","author":"JN Anastas","year":"2015","unstructured":"Anastas JN. Functional Crosstalk Between WNT Signaling and Tyrosine Kinase Signaling in Cancer. Semin Oncol. 2015;42(6):820\u201331.","journal-title":"Semin Oncol"},{"issue":"6","key":"2546_CR76","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1038\/s41419-022-04984-6","volume":"13","author":"J Kim","year":"2022","unstructured":"Kim J, Chang IY, You HJ. Interactions between EGFR and EphA2 promote tumorigenesis through the action of Ephexin1. Cell Death Dis. 2022;13(6):528.","journal-title":"Cell Death Dis"},{"key":"2546_CR77","doi-asserted-by":"crossref","unstructured":"Stallaert W, Br\u00fcggemann Y, Sabet O, Baak L, Gattiglio M, Bastiaens PIH. Contact inhibitory Eph signaling suppresses EGF-promoted cell migration by decoupling EGFR activity from vesicular recycling. Sci Signal. 2018;11(541).","DOI":"10.1126\/scisignal.aat0114"},{"issue":"7","key":"2546_CR78","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1093\/carcin\/bgp097","volume":"30","author":"K Kawaguchi","year":"2009","unstructured":"Kawaguchi K, Murakami H, Taniguchi T, Fujii M, Kawata S, Fukui T, et al. Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells. Carcinogenesis. 2009;30(7):1097\u2013105.","journal-title":"Carcinogenesis"},{"issue":"9","key":"2546_CR79","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1038\/nrc3792","volume":"14","author":"FJ Sulzmaier","year":"2014","unstructured":"Sulzmaier FJ, Jean C, Schlaepfer DD. FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer. 2014;14(9):598\u2013610.","journal-title":"Nat Rev Cancer"},{"issue":"5","key":"2546_CR80","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41568-021-00340-6","volume":"21","author":"JC Dawson","year":"2021","unstructured":"Dawson JC, Serrels A, Stupack DG, Schlaepfer DD, Frame MC. Targeting FAK in anticancer combination therapies. Nat Rev Cancer. 2021;21(5):313\u201324.","journal-title":"Nat Rev Cancer"},{"key":"2546_CR81","doi-asserted-by":"crossref","unstructured":"Chuang HH, Zhen YY, Tsai YC, Chuang CH, Hsiao M, Huang MS, et al. FAK in cancer: from mechanisms to therapeutic strategies. Int J Mol Sci. 2022;23(3).","DOI":"10.3390\/ijms23031726"},{"issue":"36","key":"2546_CR82","doi-asserted-by":"publisher","first-page":"6370","DOI":"10.1038\/s41388-019-0883-6","volume":"38","author":"Y Cui","year":"2019","unstructured":"Cui Y, Groth S, Troutman S, Carlstedt A, Sperka T, Riecken LB, et al. The NF2 tumor suppressor merlin interacts with Ras and RasGAP, which may modulate Ras signaling. Oncogene. 2019;38(36):6370\u201381.","journal-title":"Oncogene"},{"issue":"237","key":"2546_CR83","doi-asserted-by":"publisher","first-page":"237ra68","DOI":"10.1126\/scitranslmed.3008639","volume":"6","author":"IM Shapiro","year":"2014","unstructured":"Shapiro IM, Kolev VN, Vidal CM, Kadariya Y, Ring JE, Wright Q, et al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Transl Med. 2014;6(237):237ra68.","journal-title":"Sci Transl Med."},{"issue":"17\u201318","key":"2546_CR84","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1101\/gad.317354.118","volume":"32","author":"C Chiasson-MacKenzie","year":"2018","unstructured":"Chiasson-MacKenzie C, Morris ZS, Liu CH, Bradford WB, Koorman T, McClatchey AI. Merlin\/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface. Genes Dev. 2018;32(17\u201318):1201\u201314.","journal-title":"Genes Dev"},{"key":"2546_CR85","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.matbio.2021.09.001","volume":"103\u2013104","author":"AC Finney","year":"2021","unstructured":"Finney AC, Scott ML, Reeves KA, Wang D, Alfaidi M, Schwartz JC, et al. EphA2 signaling within integrin adhesions regulates fibrillar adhesion elongation and fibronectin deposition. Matrix Biol. 2021;103\u2013104:1\u201321.","journal-title":"Matrix Biol"},{"issue":"7","key":"2546_CR86","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1091\/mbc.e10-08-0725","volume":"22","author":"TB Deramaudt","year":"2011","unstructured":"Deramaudt TB, Dujardin D, Hamadi A, Noulet F, Kolli K, De Mey J, et al. FAK phosphorylation at Tyr-925 regulates cross-talk between focal adhesion turnover and cell protrusion. Mol Biol Cell. 2011;22(7):964\u201375.","journal-title":"Mol Biol Cell"},{"issue":"5","key":"2546_CR87","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1083\/jcb.200212114","volume":"160","author":"DA Hsia","year":"2003","unstructured":"Hsia DA, Mitra SK, Hauck CR, Streblow DN, Nelson JA, Ilic D, et al. Differential regulation of cell motility and invasion by FAK. J Cell Biol. 2003;160(5):753\u201367.","journal-title":"J Cell Biol"},{"issue":"5","key":"2546_CR88","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1083\/jcb.200904054","volume":"187","author":"EJ Ezratty","year":"2009","unstructured":"Ezratty EJ, Bertaux C, Marcantonio EE, Gundersen GG. Clathrin mediates integrin endocytosis for focal adhesion disassembly in migrating cells. J Cell Biol. 2009;187(5):733\u201347.","journal-title":"J Cell Biol"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-022-02546-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-022-02546-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-022-02546-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T17:13:39Z","timestamp":1670260419000},"score":1,"resource":{"primary":{"URL":"https:\/\/jeccr.biomedcentral.com\/articles\/10.1186\/s13046-022-02546-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,5]]},"references-count":88,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["2546"],"URL":"https:\/\/doi.org\/10.1186\/s13046-022-02546-4","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,5]]},"assertion":[{"value":"1 September 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"<i>In vivo<\/i> experiments were performed according to protocols approved by the Institutional Review Board of Thomas Jefferson University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"333"}}