RRC ID 58276
Author Sugimoto K, Ichikawa-Tomikawa N, Kashiwagi K, Endo C, Tanaka S, Sawada N, Watabe T, Higashi T, Chiba H.
Title Cell adhesion signals regulate the nuclear receptor activity.
Journal Proc Natl Acad Sci U S A
Abstract 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 γ (RARγ) and the estrogen receptor α (ERα) 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.
Volume 116(49)
Pages 24600-24609
Published 2019-12-3
DOI 10.1073/pnas.1913346116
PII 1913346116
PMID 31740618
PMC PMC6900646
MeSH Animals Cell Adhesion / physiology* Cell Line Claudins / genetics Claudins / metabolism* Estrogen Receptor alpha / metabolism Gene Expression Regulation Humans Mice Mutation Phosphatidylinositol 3-Kinases / metabolism Phosphorylation Protein Domains Proto-Oncogene Proteins c-akt / metabolism Receptors, Cytoplasmic and Nuclear / metabolism* Receptors, Retinoic Acid / genetics Receptors, Retinoic Acid / metabolism Signal Transduction Tyrosine / genetics src-Family Kinases / metabolism
IF 9.412
Times Cited 0
DNA material CSII-EF-MCS-IRES2-Venus (RDB04384) pCMV-VSV-G-RSV-Rev (RDB04393)
Human and Animal Cells BRC4(AES0008)