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PAK6 phosphorylates 14-3-3γ to regulate steady state phosphorylation of LRRK2

Civiero, L., Cogo, S., Kiekens, A., Morganti, C., Tessari, I., Lobbestael, E., Baekelandt, V., Taymans, J.-M., Chartier-Harlin, M.-C., Franchin, C., Arrigoni, G., Lewis, P. A., Piccoli, G., Bubacco, L., Cookson, M. R., Pinton, P. and Greggio, E. (2017) PAK6 phosphorylates 14-3-3γ to regulate steady state phosphorylation of LRRK2. Frontiers in Molecular Neuroscience, 10. 417. ISSN 1662-5099

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To link to this item DOI: 10.3389/fnmol.2017.00417

Abstract/Summary

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.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
ID Code:76590
Publisher:Frontiers Media

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