Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
Curr Biol. 2020 Aug 17;30(16):3141-3153.e5. doi: 10.1016/j.cub.2020.06.006. Epub 2020 Jul 2.
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.
大多数成纤维细胞生长因子 (FGFs) 通过其保守的 FGF 结构域作为受体配体发挥作用，但该结构域外的序列不同，且研究不充分。所有 FGFs 的该核心结构域由 120 个氨基酸 (aa) 组成，其两侧是长度可变的高度分化的氨基末端和羧基末端序列。果蝇的 FGF 基因较少，迄今为止仅鉴定出三个，分别是 pyramus (pyr)、thisbe (ths) 和 branchless (bnl)，它们都编码相对较大的 FGF 蛋白 (∼80 kDa)。我们假设果蝇和其他生物体中存在的较长 FGF 蛋白可能与原始形式有关，其中多个功能或调节特性存在于单个多肽中。在这里，我们专注于 Pyr 的分析，发现它具有跨膜结构域 (TMD) 和包含降解基序的延伸的胞内 C 末端结构域。胞内部分限制 Pyr 水平，而 TMD 促进无心脏 FGF 受体旁分泌激活的空间精度。此外，上调 Pyr 的降解基序缺失突变体表现出细胞极性缺陷，导致原肠胚形成时内陷缺陷，证明了以前未表征的细胞自主作用。总之，我们的数据表明 Pyr 是第一个被证明的跨膜 FGF，它具有细胞外和细胞内功能，并且这种特定的 FGF 蛋白的空间分布和水平受到严格调控。我们的结果表明，其他 FGF 可能像 Pyr 一样被膜固定或具有多功能性。
