title: Interrogation of a lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of fibroblast growth factor 10 (FGF10) function.
abstract: Heterozygous mutations in the gene encoding fibroblast growth factor 10 (FGF10) or its cognate receptor, FGF-receptor 2 IIIb result in two human syndromes - 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.
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
authors.forename: Marta
authors.initials: M
authors.lastname: Mikolajczak
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
authors.forename: Timothy
authors.initials: T
authors.lastname: Goodman
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Hajihosseini
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D051526:Fibroblast Growth Factor 10 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D034381:Hearing Loss / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007766:Lacrimal Apparatus Diseases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D013576:Syndactyly / Q000235:genetics / Q000378:metabolism*; D014071:Tooth Abnormalities / Q000235:genetics / Q000378:metabolism*
chemical_list: D051526:Fibroblast Growth Factor 10
keywords: LADD syndrome; fibroblast growth factors; mutation; nuclear localization