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Analysis of Protein-protein Interactions and Co-localization Between Components of Gap, Tight, and Adherens Junctions in Murine Mammary Glands

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HGF signaling regulates Claudin-3 dynamics through its C-terminal tyrosine residues

Floor Twiss¹, Michiel Oldenkamp¹, Annemieke Hiemstra¹

¹Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht; Utrecht, The Netherlands.

Tissue Barriers

|March 26, 2014

Abstract:

The hormone HGF regulates morphogenesis and regeneration of multiple organs and increased HGF signaling is strongly associated with metastatic cancer. At the cellular level, one of the distinct effects of HGF is the de-stabilization of cell-cell junctions. Several molecular mechanisms have been shown to be involved that mostly culminate at the E-cadherin adhesion complex. One of the key determinants in HGF-driven morphological changes is the actomyosin cytoskeleton whose organization and physical parameters changes upon stimulation. Here we have investigated how HGF affects the different actomyosin-associated cell-cell junction complexes, Nectin Junctions, Adherens Junctions and Tight Junctions in MDCK cells. We find that components of all complexes stay present at cell-cell contacts until their physical dissociation. We find that at cell-cell junctions, the mobility of Claudin-3, but not that of other cell-cell adhesion receptors, is affected by HGF. This depends on tyrosine residues that likely affect PDZ-domain interactions at the C-terminal tail of Claudin-3, although their phosphorylation is not directly regulated by HGF. Thus we uncovered Claudins as novel targets of HGF signaling at cell-cell junctions.

Insights

Hepatocyte Growth Factor (HGF) destabilizes cell-cell junctions, impacting cancer metastasis. This study reveals Claudins as novel targets of HGF signaling, affecting their mobility at cell junctions.

Area of Science:

Cell Biology
Molecular Biology
Biochemistry

Background:

Hepatocyte Growth Factor (HGF) is crucial for organ development and regeneration.
Increased HGF signaling correlates with metastatic cancer progression.
HGF disrupts cell-cell junctions, influencing tissue integrity and cancer spread.

Purpose of the Study:

To investigate the impact of HGF on actomyosin-associated cell-cell junction complexes (Nectin, Adherens, and Tight Junctions) in MDCK cells.
To identify specific molecular targets of HGF signaling at cell-cell junctions.

Main Methods:

Utilized Madin-Darby Canine Kidney (MDCK) cells to study HGF effects.
Analyzed the presence and dissociation of junctional complex components upon HGF stimulation.
Investigated the mobility of cell-cell adhesion receptors, including Claudin-3, using live-cell imaging techniques.
Examined the role of tyrosine residues in Claudin-3's C-terminal tail in HGF-mediated effects.

Main Results:

All actomyosin-associated cell-cell junction components remained at contacts until physical dissociation.
HGF significantly affected the mobility of Claudin-3 at cell-cell junctions, but not other adhesion receptors.
This Claudin-3 mobility change is linked to tyrosine residues and potential PDZ-domain interactions, independent of direct HGF-induced phosphorylation.

Conclusions:

Claudins are identified as novel targets of HGF signaling at cell-cell junctions.
HGF-induced alterations in Claudin-3 mobility contribute to the destabilization of cell-cell junctions.
Understanding these mechanisms provides insights into HGF's role in cancer metastasis and tissue regeneration.

Read full analysis

Keywords:

Claudin HGF signaling Tight Junction cell-cell junctions phosphorylation turnover

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