{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T10:48:32Z","timestamp":1769510912527,"version":"3.49.0"},"reference-count":42,"publisher":"Portland Press Ltd.","issue":"24","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,12,15]]},"abstract":"<jats:p>Heterozygous mutations in the gene encoding fibroblast growth factor 10 (FGF10) or its cognate receptor, FGF-receptor 2 IIIb result in two human syndromes \u2014 LADD (lacrimo-auriculo-dento-digital) and ALSG (aplasia of lacrimal and salivary glands). To date, the partial loss-of-FGF10 function in these patients has been attributed solely to perturbed paracrine signalling functions between FGF10-producing mesenchymal cells and FGF10-responsive epithelial cells. However, the functioning of a LADD-causing G138E FGF10 mutation, which falls outside its receptor interaction interface, has remained enigmatic. In the present study, we interrogated this mutation in the context of FGF10's protein sequence and three-dimensional structure, and followed the subcellular fate of tagged proteins containing this or other combinatorial FGF10 mutations, in vitro. We report that FGF10 harbours two putative nuclear localization sequences (NLSs), termed NLS1 and NLS2, which individually or co-operatively promote nuclear translocation of FGF10. Furthermore, FGF10 localizes to a subset of dense fibrillar components of the nucleolus. G138E falls within NLS1 and abrogates FGF10's nuclear translocation whilst attenuating its progression along the secretory pathway. Our findings suggest that in addition to its paracrine roles, FGF10 may normally play intracrine role\/s within FGF10-producing cells. Thus, G138E may disrupt both paracrine and intracrine function\/s of FGF10 through attenuated secretion and nuclear translocation, respectively.<\/jats:p>","DOI":"10.1042\/bcj20160441","type":"journal-article","created":{"date-parts":[[2016,10,15]],"date-time":"2016-10-15T01:39:39Z","timestamp":1476495579000},"page":"4593-4607","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Interrogation of a lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of fibroblast growth factor 10 (FGF10) function"],"prefix":"10.1042","volume":"473","author":[{"given":"Marta","family":"Mikolajczak","sequence":"first","affiliation":[{"name":"School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Goodman","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad K.","family":"Hajihosseini","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2016,12,9]]},"reference":[{"key":"2021112216331214400_BCJ-2016-0441C1","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1111\/j.1399-0004.2006.00597.x","article-title":"LADD syndrome is caused by FGF10 mutations","volume":"69","author":"Milunsky","year":"2006","journal-title":"Clin. Genet."},{"key":"2021112216331214400_BCJ-2016-0441C2","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1038\/ng1757","article-title":"Mutations in different components of FGF signaling in LADD syndrome","volume":"38","author":"Rohmann","year":"2006","journal-title":"Nat. Genet."},{"key":"2021112216331214400_BCJ-2016-0441C3","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.ijporl.2009.03.004","article-title":"Case report: aplasia of the lacrimal and major salivary glands (ALSG)","volume":"73","author":"Chapman","year":"2009","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"2021112216331214400_BCJ-2016-0441C4","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/sj.ejhg.5201762","article-title":"FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG)","volume":"15","author":"Entesarian","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"2021112216331214400_BCJ-2016-0441C5","doi-asserted-by":"publisher","first-page":"3156","DOI":"10.1101\/gad.12.20.3156","article-title":"Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless","volume":"12","author":"Min","year":"1998","journal-title":"Genes. Dev."},{"key":"2021112216331214400_BCJ-2016-0441C6","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1242\/dev.127.3.483","article-title":"An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis","volume":"127","author":"De Moerlooze","year":"2000","journal-title":"Development"},{"key":"2021112216331214400_BCJ-2016-0441C7","doi-asserted-by":"publisher","first-page":"6903","DOI":"10.1128\/MCB.00544-07","article-title":"Lacrimo-auriculo-dento-digital syndrome is caused by reduced activity of the fibroblast growth factor 10 (FGF10)-FGF receptor 2 signaling pathway","volume":"27","author":"Shams","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"2021112216331214400_BCJ-2016-0441C8","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1002\/wdev.176","article-title":"The fibroblast growth factor signaling pathway","volume":"4","author":"Ornitz","year":"2015","journal-title":"Wiley Interdiscip Rev. Dev. Biol."},{"key":"2021112216331214400_BCJ-2016-0441C9","doi-asserted-by":"publisher","first-page":"15694","DOI":"10.1074\/jbc.M601252200","article-title":"Receptor specificity of the fibroblast growth factor family: the complete mammalian FGF family","volume":"281","author":"Zhang","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021112216331214400_BCJ-2016-0441C10","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1159\/000115037","article-title":"Fibroblast growth factor signaling in cranial suture development and pathogenesis","volume":"12","author":"Hajihosseini","year":"2008","journal-title":"Front. Oral Biol."},{"key":"2021112216331214400_BCJ-2016-0441C11","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/nrc2780","article-title":"Fibroblast growth factor signalling: from development to cancer","volume":"10","author":"Turner","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"2021112216331214400_BCJ-2016-0441C12","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1016\/j.cell.2012.04.046","article-title":"Fibroblast growth factor 13 is a microtubule-stabilizing protein regulating neuronal polarization and migration","volume":"149","author":"Wu","year":"2012","journal-title":"Cell"},{"key":"2021112216331214400_BCJ-2016-0441C13","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1002\/emmm.201302698","article-title":"Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion","volume":"6","author":"Coleman","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"2021112216331214400_BCJ-2016-0441C14","doi-asserted-by":"publisher","first-page":"3869","DOI":"10.1242\/jcs.02509","article-title":"Different intracellular trafficking of FGF1 endocytosed by the four homologous FGF receptors","volume":"118","author":"Haugsten","year":"2005","journal-title":"J. Cell. Sci."},{"key":"2021112216331214400_BCJ-2016-0441C15","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1111\/j.1742-4658.2008.06316.x","article-title":"Intracellular trafficking of endogenous fibroblast growth factor-2","volume":"275","author":"Taverna","year":"2008","journal-title":"FEBS J."},{"key":"2021112216331214400_BCJ-2016-0441C16","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/ncb979","article-title":"Translokin is an intracellular mediator of FGF-2 trafficking","volume":"5","author":"Bossard","year":"2003","journal-title":"Nat. Cell. Biol."},{"key":"2021112216331214400_BCJ-2016-0441C17","doi-asserted-by":"publisher","first-page":"36303","DOI":"10.1074\/jbc.M114.619569","article-title":"Knockout of nuclear high molecular weight FGF2 isoforms in mice modulates bone and phosphate homeostasis","volume":"289","author":"Homer-Bouthiette","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2021112216331214400_BCJ-2016-0441C18","doi-asserted-by":"publisher","first-page":"4364","DOI":"10.1128\/MCB.15.8.4364","article-title":"Nucleolar association of fibroblast growth factor 3 via specific sequence motifs has inhibitory effects on cell growth","volume":"15","author":"Kiefer","year":"1995","journal-title":"Mol. Cell. Biol."},{"key":"2021112216331214400_BCJ-2016-0441C19","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1186\/1756-0500-5-513","article-title":"A simple protocol for the subcellular fractionation of skeletal muscle cells and tissue","volume":"5","author":"Dimauro","year":"2012","journal-title":"BMC Res. Notes"},{"key":"2021112216331214400_BCJ-2016-0441C20","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/S0925-4773(01)00656-6","article-title":"Expression patterns of fibroblast growth factors-18 and -20 in mouse embryos is suggestive of novel roles in calvarial and limb development","volume":"113","author":"Hajihosseini","year":"2002","journal-title":"Mech. Dev."},{"key":"2021112216331214400_BCJ-2016-0441C21","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/j.mcn.2008.01.008","article-title":"Localization and fate of Fgf10-expressing cells in the adult mouse brain implicate Fgf10 in control of neurogenesis","volume":"37","author":"Hajihosseini","year":"2008","journal-title":"Mol. Cell. Neurosci."},{"key":"2021112216331214400_BCJ-2016-0441C22","doi-asserted-by":"publisher","first-page":"2060","DOI":"10.1016\/j.jmb.2015.10.023","article-title":"Structural biology and regulation of protein import into the nucleus","volume":"428","author":"Christie","year":"2016","journal-title":"J. Mol. Biol."},{"key":"2021112216331214400_BCJ-2016-0441C23","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1186\/1471-2105-10-202","article-title":"NLStradamus: a simple hidden Markov model for nuclear localization signal prediction","volume":"10","author":"Nguyen Ba","year":"2009","journal-title":"BMC Bioinf."},{"key":"2021112216331214400_BCJ-2016-0441C24","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1093\/bioinformatics\/btm066","article-title":"NucPred \u2014 predicting nuclear localization of proteins","volume":"23","author":"Brameier","year":"2007","journal-title":"Bioinformatics"},{"key":"2021112216331214400_BCJ-2016-0441C25","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1002\/jcb.21330","article-title":"Translocation of fibroblast growth factor-10 and its receptor into nuclei of human urothelial cells","volume":"102","author":"Kosman","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"2021112216331214400_BCJ-2016-0441C26","doi-asserted-by":"publisher","first-page":"40153","DOI":"10.1074\/jbc.M400123200","article-title":"Nuclear and nucleolar localization of 18-kDa fibroblast growth factor-2 is controlled by C-terminal signals","volume":"279","author":"Sheng","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021112216331214400_BCJ-2016-0441C27","doi-asserted-by":"publisher","first-page":"6071","DOI":"10.1021\/bi047403m","article-title":"Two nuclear localization signals required for transport from the cytosol to the nucleus of externally added FGF-1 translocated into cells","volume":"44","author":"Wesche","year":"2005","journal-title":"Biochemistry"},{"key":"2021112216331214400_BCJ-2016-0441C28","doi-asserted-by":"publisher","first-page":"15918","DOI":"10.1074\/jbc.271.27.15918","article-title":"Structure and expression of the rat mRNA encoding a novel member of the fibroblast growth factor family","volume":"271","author":"Yamasaki","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2021112216331214400_BCJ-2016-0441C29","doi-asserted-by":"publisher","first-page":"2211","DOI":"10.1038\/sj.onc.1201383","article-title":"Mouse fibroblast growth factor 10: cDNA cloning, protein characterization, and regulation of mRNA expression","volume":"15","author":"Beer","year":"1997","journal-title":"Oncogene"},{"key":"2021112216331214400_BCJ-2016-0441C30","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.ydbio.2010.11.029","article-title":"Fibroblast growth factor 10 regulates Meckel's cartilage formation during early mandibular morphogenesis in rats","volume":"350","author":"Terao","year":"2011","journal-title":"Dev. Biol."},{"key":"2021112216331214400_BCJ-2016-0441C31","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1242\/dev.051680","article-title":"FGF10 controls the patterning of the tracheal cartilage rings via Shh","volume":"138","author":"Sala","year":"2011","journal-title":"Development"},{"key":"2021112216331214400_BCJ-2016-0441C32","doi-asserted-by":"publisher","first-page":"ra55","DOI":"10.1126\/scisignal.2000304","article-title":"Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis","volume":"2","author":"Makarenkova","year":"2009","journal-title":"Sci. Signal."},{"key":"2021112216331214400_BCJ-2016-0441C33","doi-asserted-by":"publisher","first-page":"a000638","DOI":"10.1101\/cshperspect.a000638","article-title":"The nucleolus","volume":"3","author":"Pederson","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2021112216331214400_BCJ-2016-0441C34","doi-asserted-by":"publisher","first-page":"9419","DOI":"10.1128\/MCB.25.21.9419-9426.2005","article-title":"Direct regulation of rRNA transcription by fibroblast growth factor 2","volume":"25","author":"Sheng","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"2021112216331214400_BCJ-2016-0441C35","doi-asserted-by":"publisher","first-page":"4996","DOI":"10.1128\/MCB.21.15.4996-5007.2001","article-title":"NoBP, a nuclear fibroblast growth factor 3 binding protein, is cell cycle regulated and promotes cell growth","volume":"21","author":"Reimers","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"2021112216331214400_BCJ-2016-0441C36","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1002\/dvdy.21648","article-title":"Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model","volume":"238","author":"Hajihosseini","year":"2009","journal-title":"Dev. Dyn."},{"key":"2021112216331214400_BCJ-2016-0441C37","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.ydbio.2015.01.015","article-title":"Fgf10 is required for specification of non-sensory regions of the cochlear epithelium","volume":"400","author":"Urness","year":"2015","journal-title":"Dev. Biol."},{"key":"2021112216331214400_BCJ-2016-0441C38","doi-asserted-by":"publisher","first-page":"6170","DOI":"10.1523\/JNEUROSCI.2437-12.2013","article-title":"Fgf10-expressing tanycytes add new neurons to the appetite\/energy-balance regulating centers of the postnatal and adult hypothalamus","volume":"33","author":"Haan","year":"2013","journal-title":"J. Neurosci."},{"key":"2021112216331214400_BCJ-2016-0441C39","doi-asserted-by":"publisher","DOI":"10.1007\/s00784-016-1771-x","article-title":"Novel FGF10 mutation in autosomal dominant aplasia of lacrimal and salivary glands","author":"Seymen","year":"2016","journal-title":"Clin. Oral. Investig."},{"key":"2021112216331214400_BCJ-2016-0441C40","doi-asserted-by":"publisher","first-page":"19802","DOI":"10.1073\/pnas.0709905104","article-title":"Structural basis for reduced FGFR2 activity in LADD syndrome: implications for FGFR autoinhibition and activation","volume":"104","author":"Lew","year":"2007","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021112216331214400_BCJ-2016-0441C41","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1186\/1471-2350-9-114","article-title":"An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome","volume":"9","author":"Scheckenbach","year":"2008","journal-title":"BMC Med. Genet."},{"key":"2021112216331214400_BCJ-2016-0441C42","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1038\/ng1507","article-title":"Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands","volume":"37","author":"Entesarian","year":"2005","journal-title":"Nat. Genet."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/473\/24\/4593\/688442\/bcj-2016-0441.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/473\/24\/4593\/688442\/bcj-2016-0441.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T23:18:54Z","timestamp":1637623134000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/473\/24\/4593\/49300\/Interrogation-of-a-lacrimo-auriculo-dento-digital"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,9]]},"references-count":42,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2016,12,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bcj20160441","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,9]]}}}