缺氧诱导因子 2α（HIF2α）依赖性衔接蛋白 4（Dock4）/Rac1 信号通路调控常氧条件下黏着连接和细胞极性的形成。

HIF2α-dependent Dock4/Rac1-signaling regulates formation of adherens junctions and cell polarity in normoxia.

机构信息

Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

Extracellular Matrix and Hypoxia Research Unit, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

出版信息

Sci Rep. 2024 May 27;14(1):12153. doi: 10.1038/s41598-024-62955-7.

DOI:10.1038/s41598-024-62955-7

PMID:38802496

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11130225/

Abstract

Hypoxia-inducible factors (HIF) 1 and 2 regulate similar but distinct sets of target genes. Although HIFs are best known for their roles in mediating the hypoxia response accumulating evidence suggests that under certain conditions HIFs, particularly HIF2, may function also under normoxic conditions. Here we report that HIF2α functions under normoxic conditions in kidney epithelial cells to regulate formation of adherens junctions. HIF2α expression was required to induce Dock4/Rac1/Pak1-signaling mediating stability and compaction of E-cadherin at nascent adherens junctions. Impaired adherens junction formation in HIF2α- or Dock4-deficient cells led to aberrant cyst morphogenesis in 3D kidney epithelial cell cultures. Taken together, we show that HIF2α functions in normoxia to regulate epithelial morphogenesis.

摘要

缺氧诱导因子 (HIF) 1 和 2 调节相似但不同的靶基因。虽然 HIF 以介导缺氧反应而闻名，但越来越多的证据表明，在某些条件下，HIF，特别是 HIF2，也可能在常氧条件下发挥作用。在这里，我们报告 HIF2α 在肾脏上皮细胞中在常氧条件下发挥作用，以调节黏附连接的形成。HIF2α 的表达对于诱导 Dock4/Rac1/Pak1 信号至关重要，该信号介导新形成的黏附连接处 E-钙黏蛋白的稳定性和致密性。在 HIF2α 或 Dock4 缺陷细胞中黏附连接形成受损导致 3D 肾脏上皮细胞培养物中异常的囊肿形态发生。总之，我们表明 HIF2α 在常氧条件下发挥作用，调节上皮形态发生。