PAK kinases targets sortilin and modulates its sorting

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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.

TidsskriftMolecular and Cellular Biology
Antal sider16
StatusUdgivet - feb. 2020


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