期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 49, 页码 24600-24609出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1913346116
关键词
tight junction; claudin; signal transduction; retinoic acid receptor; estrogen receptor
资金
- JSPS KAKENHI Grant [17K08699, 17K17978]
- Uehara Memorial Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [17K08699, 17K17978] Funding Source: KAKEN
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.
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