PAK kinases targets sortilin and modulates its sorting

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

The multifunctional type-1 receptor sortilin is involved in endocytosis and intracellular transport of ligands. The short intracellular domain of sortilin binds several cytoplasmic adaptor proteins (e.g. the AP-1 complex and GGA1-3) most of which target two well-defined motifs; a C-terminal acidic cluster-dileucine motif and an YxxΦ motif in the proximal third of the domain. Both motifs contribute to endocytosis as well as Golgi-endosome trafficking of sortilin. The C-terminal acidic cluster harbors a serine residue, which is subject to phosphorylation by casein-kinase. Phosphorylation of this serine residue is known to modulate adaptor-binding to sortilin. Here we show that the cytoplasmic domain of sortilin also engages the Rac-p21-Activated Kinases 1-3 (PAK1-3) via a binding segment that includes a tyrosine-based motif, also encompassing a serine residue. We further demonstrate that PAK1-3 specifically phosphorylate this serine residue and that this phosphorylation alters the affinity for AP-1 binding and consequently changes the intracellular localization of sortilin as a result of modulated trafficking. Our findings suggest that trafficking of ligands bound to sortilin is in part regulated by group A PAK kinases which are downstream effectors of Rho GTPases and are known to affect a variety of processes by remodeling the cytoskeleton, and by promoting gene transcription and cell survival.

Original languageEnglish
Article numbere00411-19
JournalMolecular and Cellular Biology
Volume40
Issue3
Number of pages16
ISSN0270-7306
DOIs
Publication statusPublished - Feb 2020

Bibliographical note

Copyright © 2020 Pallesen et al.

See relations at Aarhus University Citationformats

ID: 173286379