GSK3 and Polo-like kinase regulate ADAM13 function during cranial neural crest cell migration

Area of Science:

• Molecular Biology
• Developmental Biology
• Cell Biology

Background:

• ADAMs are metalloproteases regulating cell signaling and adhesion.
• ADAM13 is crucial for cranial neural crest (CNC) cell migration via proteolysis and nuclear signaling.
• The nuclear function of ADAM13 and its regulation are not fully understood.

Purpose of the Study:

• To investigate the regulatory mechanisms of ADAM13's nuclear function in CNC migration.
• To identify kinases that modulate ADAM13 activity and its role in transcription.
• To explore the interplay between ADAM13 phosphorylation and its downstream targets.

Main Methods:

• Phosphorylation site analysis of ADAM13.
• Inhibition of GSK3 and Polo-like kinase (Plk) in CNC migration models.
• Rescue experiments using phosphomimetic ADAM13 mutants.
• Analysis of calpain-8 expression and its impact on CNC migration.

Main Results:

• ADAM13's promotion of CNC migration is regulated by GSK3 and Plk phosphorylation.
• Inhibition of GSK3 or Plk impairs CNC migration, but proteolysis and nuclear translocation remain unaffected.
• Phosphorylation events are distinct from ADAM13's proteolytic and γ-secretase cleavage activities.
• Calpain-8 expression can restore CNC migration in Plk-deficient cells, suggesting impaired ADAM13 nuclear function.

Conclusions:

• GSK3 and Plk phosphorylation are critical regulators of ADAM13's role in CNC migration.
• These phosphorylations modulate ADAM13's nuclear transcriptional activity rather than its proteolytic or cleavage functions.
• Dysregulation of ADAM13 phosphorylation impacts CNC migration by affecting its nuclear targets, such as calpain-8.