FGF Pyramus Has a Transmembrane Domain and Cell-Autonomous Function in Polarity

Curr Biol. 2020 Aug 17;30(16):3141-3153.e5. doi: 10.1016/j.cub.2020.06.006. Epub 2020 Jul 2.

Abstract

Most fibroblast growth factors (FGFs) function as receptor ligands through their conserved FGF domain, but sequences outside this domain vary and are not well studied. This core domain of 120 amino acids (aa) is flanked in all FGFs by highly divergent amino-terminal and carboxy-terminal sequences of variable length. Drosophila has fewer FGF genes, with only three identified to date, pyramus (pyr), thisbe (ths), and branchless (bnl), and all three encoding relatively large FGF proteins (∼80 kDa). We hypothesized that the longer FGF proteins present in Drosophila and other organisms may relate to an ancestral form, in which multiple functions or regulatory properties are present within a single polypeptide. Here, we focused analysis on Pyr, finding that it harbors a transmembrane domain (TMD) and extended C-terminal intracellular domain containing a degron. The intracellular portion limits Pyr levels, whereas the TMD promotes spatial precision in the paracrine activation of Heartless FGF receptor. Additionally, degron deletion mutants that upregulate Pyr exhibit cell polarity defects that lead to invagination defects at gastrulation, demonstrating a previously uncharacterized cell-autonomous role. In summary, our data show that Pyr is the first demonstrated transmembrane FGF, that it has both extracellular and intracellular functions, and that spatial distribution and levels of this particular FGF protein are tightly regulated. Our results suggest that other FGFs may be membrane tethered or multifunctional like Pyr.

Keywords: Drosophila melanogaster; FGF signaling; Pyr; TMD; Ths; branchless; degron; pyramus; thisbe; transmembrane domain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / metabolism*
  • Cell Movement
  • Cell Polarity*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / physiology*
  • Female
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Gastrulation
  • Male
  • Mesoderm / cytology
  • Mesoderm / physiology*
  • Signal Transduction

Substances

  • Drosophila Proteins
  • Fibroblast Growth Factors