PAK4 promotes vertex remodeling to maintain epithelial integrity and barrier function

Area of Science:

• Cell Biology
• Epithelial Biology
• Molecular Mechanisms

Background:

• Cell-cell junctions are vital for epithelial integrity and barrier function.
• Mechanisms controlling the remodeling of these junctions are not fully understood.

Purpose of the Study:

• To investigate the role of the junctional kinase PAK4 in vertex remodeling.
• To elucidate the interplay between PAK4, Afadin, and epithelial barrier maintenance.

Main Methods:

• Utilized MDCK cells and Xenopus embryos for studying cell-cell junctions.
• Employed techniques including gene knockout (KO), protein inhibition, and expression of protein fragments.
• Analyzed junctional integrity, vertex morphology, barrier function, and protein localization (PAK4, Afadin, myosin II).

Main Results:

• PAK4 accumulates at multicellular vertices and is required for proper vertex remodeling.
• PAK4 deficiency leads to increased higher-order vertices, junctional discontinuities, and impaired barrier function.
• Afadin is essential for PAK4 recruitment; PAK4 and Afadin cooperate to maintain epithelial integrity and barrier function.
• PAK4-deficient cells show increased junctional myosin II accumulation, suggesting impaired myosin phosphatase activity.

Conclusions:

• PAK4 and Afadin act in concert to regulate vertex remodeling, thereby maintaining epithelial integrity and barrier function.
• Dysregulation of PAK4-mediated vertex remodeling compromises epithelial barrier properties.
• The findings highlight a novel mechanism involving PAK4 and Afadin in epithelial homeostasis.