ArticleFrontiers in molecular neuroscience2017
PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2.
Article in Frontiers in molecular neuroscience, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 54 citations in OpenAlex.
- 14-3-3 proteins: Regulators of cardiac excitation-contraction coupling and stress responses.The Journal of physiology · 2026Review
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- CCL2 and PAK6 as Candidate Biomarkers of Neuroinflammation in Parkinson's Disease: An Integrated Machine Learning and Single-Nucleus Transcriptomic Study.Brain sciences · 2026Article
- Affective phenotypes in heterozygousFrontiers in genetics · 2025Article
- 14-3-3 phosphorylation inhibits 14-3-3θ's ability to regulate LRRK2 kinase activity and toxicity.Human molecular genetics · 2024Article
- PAK6 rescues pathogenic LRRK2-mediated ciliogenesis and centrosomal cohesion defects in a mutation-specific manner.Cell death & disease · 2024Article
- Prospective Role of PAK6 and 14-3-3γ as Biomarkers for Parkinson's Disease.Journal of Parkinson's disease · 2024Article
- Insights into the cellular consequences of LRRK2-mediated Rab protein phosphorylation.Biochemical Society transactions · 2023Review
- 14-3-3γ haploinsufficiency leads to altered dopamine pathway and Parkinson's disease-like motor incoordination in mice.Molecular brain · 2023Article
- PAK6-mediated phosphorylation of PPP2R2C regulates LRRK2-PP2A complex formation.Frontiers in molecular neuroscience · 2023Article
- Dementia with Lewy bodies post-mortem brains reveal differentially methylated CpG sites with biomarker potential.Communications biology · 2022Article
- Current Insights on Neurodegeneration by the Italian Proteomics Community.Biomedicines · 2022Review
- LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson's disease.NPJ Parkinson's disease · 2022Article
- Evaluation of Current Methods to Detect Cellular Leucine-Rich Repeat Kinase 2 (LRRK2) Kinase Activity.Journal of Parkinson's disease · 2022Article
- Phosphorylated and Phosphomimicking Variants May Differ-A Case Study of 14-3-3 Protein.Frontiers in chemistry · 2022Article
- Article
- Pathways to Parkinson's disease: a spotlight on 14-3-3 proteins.NPJ Parkinson's disease · 2021Review
- In silico comparative analysis of LRRK2 interactomes from brain, kidney and lung.Brain research · 2021Article
- Loss of p21-activated kinase Mbt/PAK4 causes Parkinson-like phenotypes in Drosophila.Disease models & mechanisms · 2021Article
- 14-3-3 Proteins: Novel Pharmacological Targets in Neurodegenerative Diseases.Trends in pharmacological sciences · 2021Review
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Authors and funding
17 authors at 8 institutions in 5 countries.
Funding
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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