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

Civiero, L; Cogo, S; Kiekens, A; Morganti, C; Tessari, I; Lobbestael, E; Baekelandt, V; ... Greggio, E; + view all (2017) PAK6 Phosphorylates 14-3-3 gamma to Regulate Steady State Phosphorylation of LRRK2. Frontiers in Molecular Neuroscience , 10 , Article 417. 10.3389/fnmol.2017.00417. Green open access

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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.

Type: Article
Title: PAK6 Phosphorylates 14-3-3 gamma to Regulate Steady State Phosphorylation of LRRK2
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fnmol.2017.00417
Publisher version: http://doi.org/10.3389/fnmol.2017.00417
Language: English
Additional information: Copyright © 2017 Civiero, Cogo, Kiekens, Morganti, Tessari, Lobbestael, Baekelandt, Taymans, Chartier-Harlin, Franchin, Arrigoni, Lewis, Piccoli, Bubacco, Cookson, Pinton and Greggio. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: PAK6, 14-3-3, LRRK2, Parkinson’s disease, phosphorylation
URI: http://discovery.ucl.ac.uk/id/eprint/10049913
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