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PAK Kinases Target Sortilin and Modulate Its Sorting.

Lone Tjener Pallesen1, Camilla Gustafsen2, Jacob Flyvholm Cramer3

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Sortilin receptor trafficking is regulated by phosphorylation. Group A PAK kinases phosphorylate sortilin, altering adaptor protein binding and changing intracellular localization for ligand transport.

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Receptor Trafficking

Background:

  • Sortilin, a multifunctional type 1 receptor, mediates endocytosis and intracellular transport of ligands.
  • Its intracellular domain binds adaptor proteins via dileucine and YXXΦ motifs, influencing endocytosis and Golgi-endosome trafficking.
  • Casein kinase phosphorylation of a serine residue in the acidic cluster motif modulates adaptor binding.

Purpose of the Study:

  • To investigate the interaction between sortilin's cytoplasmic domain and Rac-p21-activated kinases (PAK1-3).
  • To determine if PAK1-3 phosphorylate sortilin and how this affects adaptor protein binding and intracellular localization.

Main Methods:

  • Investigated the binding segment of sortilin's cytoplasmic domain for PAK1-3 engagement.
  • Demonstrated specific phosphorylation of a serine residue within this segment by PAK1-3.
  • Assessed the impact of this phosphorylation on AP-1 binding affinity and sortilin's intracellular localization.

Main Results:

  • The cytoplasmic domain of sortilin engages PAK1-3 via a tyrosine-based motif containing a serine residue.
  • PAK1-3 specifically phosphorylate this serine residue on sortilin.
  • This phosphorylation event alters the affinity for AP-1 complex binding, consequently modifying sortilin's intracellular localization.

Conclusions:

  • Group A PAK kinases regulate sortilin trafficking through specific phosphorylation.
  • Modulated adaptor protein binding by PAK-mediated phosphorylation influences the intracellular transport of sortilin and its bound ligands.
  • This provides a novel mechanism linking Rho GTPase signaling to receptor-mediated endosomal transport pathways.