Interrogation of a Lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of Fibroblast growth factor 10 (FGF10) function

Marta Mikolajczak, Goodman Timothy, Mohammad Hajihosseini (Group Leader)

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Heterozygous mutations in the gene encoding fibroblast growth factor 10 (FGF10) or its cognate receptor, FGF-receptor 2 IIIb (FGFR2-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 this 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, 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.
Original languageEnglish
Article numberBCJ20160441
JournalBiochemical Journal
Issue number24
Early online date14 Oct 2016
Publication statusE-pub ahead of print - 14 Oct 2016

Keywords / Materials (for Non-textual outputs)

  • LADD syndrome
  • fibroblast growth factors
  • mutation
  • nuclear localisation


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