PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2

• Published in: Frontiers in molecular neuroscience Vol. 10; p. 417
• Main Authors: Civiero, Laura, Cogo, Susanna, Kiekens, Anneleen, Morganti, Claudia, Tessari, Isabella, Lobbestael, Evy, Baekelandt, Veerle, Taymans, Jean-Marc, Chartier-Harlin, Marie-Christine, Franchin, Cinzia, Arrigoni, Giorgio, Lewis, Patrick A., Piccoli, Giovanni, Bubacco, Luigi, Cookson, Mark R., Pinton, Paolo, Greggio, Elisa
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 14.12.2017; Frontiers Media S.A
• Subjects: 14-3-3; 14-3-3 protein; Age; Binding sites; Cell adhesion & migration; Cytoskeleton; Dephosphorylation; Guanosine triphosphatases; Kinases; Leucine; LRRK2; LRRK2 protein; Movement disorders; Mutation; Neurodegeneration; Neurodegenerative diseases; Neuroscience; Neurosciences; PAK6; Parkinson's disease; Phosphatase; Phosphorylation; Plasmids; Proteins; Rac1 protein; Regulation; Signal transduction; Therapeutic applications; France; Italy; 14-3-3; PAK6; Parkinson's disease; phosphorylation; LRRK2
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2017.00417

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that PD-associated mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of the downstream signaling pathways. We have previously demonstrated that one LRRK2 binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and this phosphorylation serves as a switch to dissociate the chaperone from client proteins including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935, causing LRRK2 dephosphorylation. To address whether these interactions are relevant in a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism of 14-3-3/LRRK2 complex in the brain.