Cell adhesion signals regulate the nuclear receptor activity
Cell adhesion signals regulate the nuclear receptor activity
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DOI：
10.1073/pnas.1913346116
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发表时间：
2019-12-03
影响因子：
11.1
通讯作者：
Chiba, Hideki
中科院分区：
文献类型：
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作者：
Sugimoto, Kotaro;Ichikawa-Tomikawa, Naoki;Chiba, Hideki
细胞粘附对于多细胞生物中适当的组织结构和功能至关重要。细胞粘附分子不仅维持组织完整性，还具有有助于细胞生长、存活、分化、极性和迁移等多种细胞事件的信号传导特性；然而，潜在的分子基础仍然不明确。在这里，我们确定紧密连接蛋白claudin-6 (CLDN6) 启动的细胞粘附信号调节核受体活性。我们发现 CLDN6 以第二种胞外域依赖性和 Y196/200 依赖性方式招募并激活 Src 家族激酶 (SFK)，并且 SFK 反过来在 Y196/200 处磷酸化 CLDN6。我们证明 CLDN6/SFK/PI3K/AKT 轴靶向视黄酸受体 γ (RAR γ) 和雌激素受体 α (ER α) 中的 AKT 磷酸化位点并刺激它们的活性。有趣的是，这些磷酸化基序在人类核受体的 48 个成员中的 14 个中是保守的。我们提出，不同的细胞粘附和核受体信号传导之间存在类似的联系，协调多种生理和病理过程。
Cell adhesion is essential for proper tissue architecture and function in multicellular organisms. Cell adhesion molecules not only maintain tissue integrity but also possess signaling properties that contribute to diverse cellular events such as cell growth, survival, differentiation, polarity, and migration; however, the underlying molecular basis remains poorly defined. Here we identify that the cell adhesion signal initiated by the tight-junction protein claudin-6 (CLDN6) regulates nuclear receptor activity. We show that CLDN6 recruits and activates Src-family kinases (SFKs) in second extracellular domain-dependent and Y196/200-dependent manners, and SFKs in turn phosphorylate CLDN6 at Y196/200. We demonstrate that the CLDN6/SFK/PI3K/AKT axis targets the AKT phosphorylation sites in the retinoic acid receptor gamma (RAR gamma) and the estrogen receptor alpha (ER alpha) and stimulates their activities. Interestingly, these phosphorylation motifs are conserved in 14 of 48 members of human nuclear receptors. We propose that a similar link between diverse cell adhesion and nuclear receptor signalings coordinates a wide variety of physiological and pathological processes.