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Published August 17, 2020 | Supplemental Material + Accepted Version
Journal Article Open

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


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.

Additional Information

© 2020 Elsevier Inc. Received 17 March 2020, Revised 13 May 2020, Accepted 1 June 2020, Available online 2 July 2020. We thank Fumio Matsuzaki, David Kosman, and Jennifer Zallen for providing constructs or antibodies and Frank Macabenta and Kai Zinn for comments on the manuscript. This study was supported by grants R35GM118146 from the National Institute of General Medical Sciences (NIGMS) to A.S., PF-15-202-01-DDC from the American Cancer Society to V.S., and the Chen Director's Award from the Tianqiao and Chrissy Chen Institute for Neuroscience to A.S. Author Contributions: A.S., V.S., and J.S. conceived the project and planned the experimental approach. A.S. directed the project. V.S. performed all protein and cell culture studies and bioinformatic analysis of proteins and generated Pyr^(intra) antibodies and CRISPR-Cas9 mutants. J.S. performed all the stainings, quantitative analysis of imaging data, and viability studies. Data were analyzed by V.S., J.S., and A.S. The manuscript was written by V.S., J.S., and A.S. The authors declare no competing interests.

Attached Files

Accepted Version - nihms-1602630.pdf

Supplemental Material - 1-s2.0-S0960982220308228-mmc1.pdf


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August 22, 2023
December 22, 2023