Division of Endocrinology and Metabolism, Department of Medicine, and Department of Anatomy and Cell Biology, McGill University, Montreal, QC H4A 3J1, Canada.
Metabolic Disorders and Complications Program, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Mol Biol Cell. 2021 Apr 15;32(8):788-799. doi: 10.1091/mbc.E20-07-0490. Epub 2021 Feb 10.
During larval development, an inductive signal mediated by the LET-23 EGFR (epidermal growth factor receptor), specifies three of six vulva precursor cells (VPCs) to adopt vulval cell fates. An evolutionarily conserved complex consisting of PDZ domain-containing scaffold proteins LIN-2 (CASK), LIN-7 (Lin7 or Veli), and LIN-10 (APBA1 or Mint1) (LIN-2/7/10) mediates basolateral LET-23 EGFR localization in the VPCs to permit signal transmission and development of the vulva. We recently found that the LIN-2/7/10 complex likely forms at Golgi ministacks; however, the mechanism through which the complex targets the receptor to the basolateral membrane remains unknown. Here we found that overexpression of LIN-10 or LIN-7 can compensate for loss of their complex components by promoting LET-23 EGFR signaling through previously unknown complex-independent and receptor-dependent pathways. In particular, LIN-10 can independently promote basolateral LET-23 EGFR localization, and its complex-independent function uniquely requires its PDZ domains that also regulate its localization to Golgi. These studies point to a novel complex-independent function for LIN-7 and LIN-10 that broadens our understanding of how this complex regulates targeted sorting of membrane proteins.
在幼虫发育过程中，由 LET-23 EGFR（表皮生长因子受体）介导的诱导信号指定六个外阴前体细胞（VPC）中的三个采用外阴细胞命运。一个由含有 PDZ 结构域的支架蛋白 LIN-2（CASK）、LIN-7（Lin7 或 Veli）和 LIN-10（APBA1 或 Mint1）组成的进化保守复合物（LIN-2/7/10）介导 LET-23 EGFR 在 VPC 中的基底外侧定位，以允许信号转导和外阴的发育。我们最近发现，LIN-2/7/10 复合物可能在高尔基小堆栈中形成；然而，复合物将受体靶向基底外侧膜的机制仍不清楚。在这里，我们发现 LIN-10 或 LIN-7 的过表达可以通过先前未知的独立于复合物和受体依赖的途径促进 LET-23 EGFR 信号转导来补偿其复合物成分的缺失。特别是，LIN-10 可以独立地促进基底外侧 LET-23 EGFR 定位，其独立于复合物的功能独特地需要其 PDZ 结构域，该结构域还调节其向高尔基的定位。这些研究指出了 LIN-7 和 LIN-10 的一种新的独立于复合物的功能，拓宽了我们对该复合物如何调节膜蛋白靶向分选的理解。
