Interplay between phosphorylation and palmitoylation mediates plasma membrane targeting and sorting of GAP43

Autor(en): Gauthier-Kemper, Anne
Igaev, Maxim
Suendermann, Frederik
Janning, Dennis
Bruehmann, Joerg
Moschner, Katharina
Reyher, Hans-Juergen
Junge, Wolfgang 
Glebov, Konstantin
Walter, Jochen
Bakota, Lidia
Brandt, Roland 
Stichwörter: BRAIN; CALMODULIN; Cell Biology; CORTICAL-NEURONS; FATTY ACYLATION; GROWTH; IDENTIFICATION; NEUROMODULIN GAP-43; PROTEIN-KINASE-C; SEQUENCE MOTIFS; TRAFFICKING
Erscheinungsdatum: 2014
Herausgeber: AMER SOC CELL BIOLOGY
Journal: MOLECULAR BIOLOGY OF THE CELL
Volumen: 25
Ausgabe: 21
Startseite: 3284
Seitenende: 3299
Zusammenfassung: 
Phosphorylation and lipidation provide posttranslational mechanisms that contribute to the distribution of cytosolic proteins in growing nerve cells. The growth-associated protein GAP43 is susceptible to both phosphorylation and S-palmitoylation and is enriched in the tips of extending neurites. However, how phosphorylation and lipidation interplay to mediate sorting of GAP43 is unclear. Using a combination of biochemical, genetic, and imaging approaches, we show that palmitoylation is required for membrane association and that phosphorylation at Ser-41 directs palmitoylated GAP43 to the plasma membrane. Plasma membrane association decreased the diffusion constant fourfold in neuritic shafts. Sorting to the neuritic tip required palmitoylation and active transport and was increased by phosphorylation-mediated plasma membrane interaction. Vesicle tracking revealed transient association of a fraction of GAP43 with exocytic vesicles and motion at a fast axonal transport rate. Simulations confirmed that a combination of diffusion, dynamic plasma membrane interaction and active transport of a small fraction of GAP43 suffices for efficient sorting to growth cones. Our data demonstrate a complex interplay between phosphorylation and lipidation in mediating the localization of GAP43 in neuronal cells. Palmitoylation tags GAP43 for global sorting by piggybacking on exocytic vesicles, whereas phosphorylation locally regulates protein mobility and plasma membrane targeting of palmitoylated GAP43.
ISSN: 10591524
DOI: 10.1091/mbc.E13-12-0737

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