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The Src-Family Kinases SRC and BLK Contribute to the CLDN6-Adhesion Signaling

Naoki Ichikawa-Tomikawa1, Kotaro Sugimoto1, Korehito Kashiwagi1

  • 1Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.

Cells
|July 14, 2023
PubMed

Insights

Claudins (CLDNs) activate Src-family kinases (SFKs) in cell adhesion. This study identifies BLK and SRC as key SFKs essential for CLDN6-mediated epithelial differentiation and gene expression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cell adhesion molecules (integrins, cadherins, claudins) activate Src-family kinases (SFKs).
  • The molecular mechanisms linking claudin (CLDN) adhesion to SFK activation are not fully understood.
  • SFKs play critical roles in numerous physiological and pathological processes.

Purpose of the Study:

  • To identify specific SFK members involved in CLDN6-adhesion signaling.
  • To elucidate the molecular interactions between CLDN6 and SFKs.
  • To determine the functional significance of SFK involvement in CLDN6-mediated cellular events.

Main Methods:

  • Expression analysis of SFK subtypes in F9 cells during epithelial differentiation.
  • Immunoprecipitation assays to detect CLDN6-SFK complex formation.
  • Pull-down assays using recombinant BLK, SRC, and CLDN6 C-terminal peptides.
  • Phenotypic comparison of knockout cell lines (F9:Cldn6:Blk-/- and F9:Cldn6:Src-/-) with wild-type and F9:Cldn6 cells.

Main Results:

  • BLK and SRC were highly expressed and localized with CLDN6 at cell borders during differentiation.
  • BLK and SRC directly bind to the C-terminal cytoplasmic domain of CLDN6 (CLDN6C) in a phosphotyrosine-independent manner.
  • BLK and SRC are essential for CLDN6-induced epithelial differentiation and retinoid acid receptor target gene expression.

Conclusions:

  • Specific SFK members, BLK and SRC, directly interact with CLDN6.
  • BLK and SRC are critical mediators of CLDN6-driven epithelial differentiation.
  • These findings reveal a novel mechanism of CLDN-adhesion signaling involving selective SFK participation.
Keywords:
SFKcell adhesion signalclaudinepithelial differentiationnon-receptor tyrosine kinasessignal transductiontight junction

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