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高刺猬信号通过一个多激酶依赖的开关转导，该开关控制 GPCR smoothened 的顶底分布。

High hedgehog signaling is transduced by a multikinase-dependent switch controlling the apico-basal distribution of the GPCR smoothened.

机构信息

Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France.

出版信息

Elife. 2022 Sep 9;11:e79843. doi: 10.7554/eLife.79843.

DOI:10.7554/eLife.79843
PMID:36083801
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9462849/
Abstract

The oncogenic G-protein-coupled receptor (GPCR) Smoothened (SMO) is a key transducer of the hedgehog (HH) morphogen, which plays an essential role in the patterning of epithelial structures. Here, we examine how HH controls SMO subcellular localization and activity in a polarized epithelium using the wing imaginal disc as a model. We provide evidence that HH promotes the stabilization of SMO by switching its fate after endocytosis toward recycling. This effect involves the sequential and additive action of protein kinase A, casein kinase I, and the Fused (FU) kinase. Moreover, in the presence of very high levels of HH, the second effect of FU leads to the local enrichment of SMO in the most basal domain of the cell membrane. Together, these results link the morphogenetic effects of HH to the apico-basal distribution of SMO and provide a novel mechanism for the regulation of a GPCR.

摘要

致癌的 G 蛋白偶联受体 (GPCR) Smoothened (SMO) 是 hedgehog (HH) 形态发生素的关键转导蛋白，在上皮结构的模式形成中起着至关重要的作用。在这里，我们使用翅膀 imaginal 盘作为模型，研究了 HH 如何控制极化上皮中的 SMO 亚细胞定位和活性。我们提供的证据表明，HH 通过在胞吞作用后将 SMO 的命运从内吞作用转变为再循环，从而促进 SMO 的稳定。这种效应涉及蛋白激酶 A、酪蛋白激酶 I 和融合 (FU) 激酶的顺序和累加作用。此外，在 HH 水平非常高的情况下，FU 的第二种效应导致 SMO 在细胞膜的最基底域中局部富集。总之，这些结果将 HH 的形态发生效应与 SMO 的顶底分布联系起来，并为 GPCR 的调节提供了一种新的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a861/9462849/b823caf274b1/elife-79843-sa2-fig2.jpg
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