PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2
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 e...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-12-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00417/full |
| _version_ | 1828848081857150976 |
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| author | Laura Civiero Susanna Cogo Susanna Cogo Anneleen Kiekens Claudia Morganti Isabella Tessari Evy Lobbestael Veerle Baekelandt Jean-Marc Taymans Jean-Marc Taymans Marie-Christine Chartier-Harlin Marie-Christine Chartier-Harlin Cinzia Franchin Cinzia Franchin Giorgio Arrigoni Giorgio Arrigoni Patrick A. Lewis Giovanni Piccoli Luigi Bubacco Mark R. Cookson Paolo Pinton Elisa Greggio |
| author_facet | Laura Civiero Susanna Cogo Susanna Cogo Anneleen Kiekens Claudia Morganti Isabella Tessari Evy Lobbestael Veerle Baekelandt Jean-Marc Taymans Jean-Marc Taymans Marie-Christine Chartier-Harlin Marie-Christine Chartier-Harlin Cinzia Franchin Cinzia Franchin Giorgio Arrigoni Giorgio Arrigoni Patrick A. Lewis Giovanni Piccoli Luigi Bubacco Mark R. Cookson Paolo Pinton Elisa Greggio |
| author_sort | Laura Civiero |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T22:22:49Z |
| format | Article |
| id | doaj.art-43e5922eb9114fafb29c015560ca1687 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-12T22:22:49Z |
| publishDate | 2017-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-43e5922eb9114fafb29c015560ca16872022-12-22T00:09:51ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-12-011010.3389/fnmol.2017.00417327661PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2Laura Civiero0Susanna Cogo1Susanna Cogo2Anneleen Kiekens3Claudia Morganti4Isabella Tessari5Evy Lobbestael6Veerle Baekelandt7Jean-Marc Taymans8Jean-Marc Taymans9Marie-Christine Chartier-Harlin10Marie-Christine Chartier-Harlin11Cinzia Franchin12Cinzia Franchin13Giorgio Arrigoni14Giorgio Arrigoni15Patrick A. Lewis16Giovanni Piccoli17Luigi Bubacco18Mark R. Cookson19Paolo Pinton20Elisa Greggio21Department of Biology, University of Padova, Padova, ItalyDepartment of Biology, University of Padova, Padova, ItalySchool of Pharmacy, University of Reading, Reading, United KingdomDepartment of Biology, University of Padova, Padova, ItalyDepartment of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, ItalyDepartment of Biology, University of Padova, Padova, ItalyLaboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, BelgiumLaboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, BelgiumUniversité de Lille, Institut National de la Santé et de la Recherche Médicale, CHU Lille, UMR-S1172, JPArc, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, FranceInstitut National de la Santé et de la Recherche Médicale, UMR-S 1172, Team “Early Stages of Parkinson's Disease”, Lille, FranceUniversité de Lille, Institut National de la Santé et de la Recherche Médicale, CHU Lille, UMR-S1172, JPArc, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, FranceInstitut National de la Santé et de la Recherche Médicale, UMR-S 1172, Team “Early Stages of Parkinson's Disease”, Lille, FranceDepartment of Biomedical Sciences, University of Padova, Padova, ItalyProteomics Center, University of Padova and Azienda Ospedaliera di Padova, Padova, ItalyDepartment of Biomedical Sciences, University of Padova, Padova, ItalyProteomics Center, University of Padova and Azienda Ospedaliera di Padova, Padova, ItalySchool of Pharmacy, University of Reading, Reading, United KingdomCenter for Integrative Biology, University of Trento, Trento, ItalyDepartment of Biology, University of Padova, Padova, Italy0Laboratory of Neurogenetics, National Institute on Aging/NIH, Bethesda, MD, United StatesDepartment of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, ItalyDepartment of Biology, University of Padova, Padova, ItalyMutations 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.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00417/fullPAK614-3-3LRRK2Parkinson's diseasephosphorylation |
| spellingShingle | Laura Civiero Susanna Cogo Susanna Cogo Anneleen Kiekens Claudia Morganti Isabella Tessari Evy Lobbestael Veerle Baekelandt Jean-Marc Taymans Jean-Marc Taymans Marie-Christine Chartier-Harlin Marie-Christine Chartier-Harlin Cinzia Franchin Cinzia Franchin Giorgio Arrigoni Giorgio Arrigoni Patrick A. Lewis Giovanni Piccoli Luigi Bubacco Mark R. Cookson Paolo Pinton Elisa Greggio PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2 Frontiers in Molecular Neuroscience PAK6 14-3-3 LRRK2 Parkinson's disease phosphorylation |
| title | PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2 |
| title_full | PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2 |
| title_fullStr | PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2 |
| title_full_unstemmed | PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2 |
| title_short | PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2 |
| title_sort | pak6 phosphorylates 14 3 3γ to regulate steady state phosphorylation of lrrk2 |
| topic | PAK6 14-3-3 LRRK2 Parkinson's disease phosphorylation |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00417/full |
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