Title |
PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2
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Published in |
Frontiers in Molecular Neuroscience, December 2017
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DOI | 10.3389/fnmol.2017.00417 |
Pubmed ID | |
Authors |
Laura Civiero, Susanna Cogo, Anneleen Kiekens, Claudia Morganti, Isabella Tessari, Evy Lobbestael, Veerle Baekelandt, Jean-Marc Taymans, Marie-Christine Chartier-Harlin, Cinzia Franchin, Giorgio Arrigoni, Patrick A. Lewis, Giovanni Piccoli, Luigi Bubacco, Mark R. Cookson, Paolo Pinton, Elisa Greggio |
Abstract |
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. |
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