AAK1-mediated phosphorylation of PDLIM5 and Talin1 promotes focal adhesion disassembly to accelerate cell migration

  • Nat Commun. 2026 May 4. doi: 10.1038/s41467-026-72501-w.
Daniela Krocianova  #  1 ,  Alexander D Dagg  #  2 ,  Rory A Clayton  2 ,  David Potesil  3 ,  Veronika Fedorova  1 ,  Adam Harmanec  1  4  5 ,  Viktoria Benova  6 ,  Veronika Bosakova  7 ,  Jonathan G G Kaufman  2 ,  Petra Martinkova  3 ,  Miroslava Alblova  8 ,  Bernard T Kelly  2 ,  Katerina Hanakova  3 ,  Pavel Roudnicky  3 ,  Stephanie J Spielman  9 ,  Jan Fric  7  10 ,  Filip Sroubek  4 ,  Josef Houser  3  11 ,  Antoni G Wrobel  12  13 ,  Evzen Boura  6 ,  David J Owen  2 ,  Zbynek Zdrahal  3 ,  Zuzana Kadlecova  14  15
Affiliations
  • 1. Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
  • 2. Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, UK.
  • 3. CEITEC, Masaryk University, Brno, Czech Republic.
  • 4. Czech Academy of Sciences, Institute of Information Theory and Automation, Prague, Czech Republic.
  • 5. Faculty of Mathematics and Physics, Charles University, Prague, Czech Republic.
  • 6. Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
  • 7. International Clinical Research Center, St. Anne's University Hospital in Brno, Brno, Czech Republic.
  • 8. Centre of Molecular Structure, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Vestec, Czech Republic.
  • 9. Childhood Cancer Data Lab, Alex's Lemonade Stand Foundation, Bala Cynwyd, PA, USA.
  • 10. Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
  • 11. Core Facility Biomolecular Interactions and Crystallization, Masaryk University, Brno, Czech Republic.
  • 12. Department of Biochemistry, University of Oxford, Oxford, UK.
  • 13. Structural Biology of Disease Processes Laboratory, The Francis Crick Institute, London, UK.
  • 14. Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. [email protected].
  • 15. Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, UK. [email protected].
  • # Contributed equally.
PMID: 42082516 DOI: 10.1038/s41467-026-72501-w
Abstract

AAK1 and BMP2K are serine/threonine kinases traditionally known for phosphorylating AP2 during clathrin-mediated endocytosis (CME), but their broader roles remained incompletely defined. Here, using motif-guided in silico, biochemical, and phosphoproteomic screens, we identify PDLIM5 and Talin1 as direct AAK1/BMP2K substrates. Despite high kinase-domain similarity, only AAK1 promotes cell migration and potentiates focal adhesion (FA) turnover. Live-cell imaging shows that AAK1 recruitment to FAs peaks as disassembly begins. The conserved AAK1 C-terminal PDZ-binding motif mediates direct, low-affinity binding to PDLIM5, providing a plausible mechanism for localized substrate access. Dynamic analyses of phospho-mimetic and phospho-null mutants support a model in which AAK1-dependent phosphorylation promotes timely release of PDLIM5 and Talin1 during FA disassembly. These findings reveal a kinase-driven contribution to FA turnover distinct from protease- and phosphatase-based mechanisms and suggest that functional divergence between AAK1 and BMP2K may provide a strategy to modulate cell migration with reduced impact on CME.

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