ArticleJournal of neurochemistry2014
Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways.
Article in Journal of neurochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 52 citations in OpenAlex.
- Cellular and systemic modifiers of alpha-synuclein proteostasis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- 14-3-3 binding maintains the Parkinson's associated kinase LRRK2 in an inactive state.Nature communications · 2025Article
- Protein Translation in the Pathogenesis of Parkinson's Disease.International journal of molecular sciences · 2024Review
- Network Analysis Performed on Transcriptomes of Parkinson's Disease Patients Reveals Dysfunction in Protein Translation.International journal of molecular sciences · 2024Article
- Structure and regulation of full-length human leucine-rich repeat kinase 1.Nature communications · 2023Article
- PAK6-mediated phosphorylation of PPP2R2C regulates LRRK2-PP2A complex formation.Frontiers in molecular neuroscience · 2023Article
- PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domain.The Biochemical journal · 2022Article
- The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity.The Journal of cell biology · 2022Article
- Article
- Modelling the functional genomics of Parkinson's disease in Caenorhabditis elegans: LRRK2 and beyond.Bioscience reports · 2021Review
- Deletion of lrrk2 causes early developmental abnormalities and age-dependent increase of monoamine catabolism in the zebrafish brain.PLoS genetics · 2021Article
- In silico comparative analysis of LRRK2 interactomes from brain, kidney and lung.Brain research · 2021Article
- Deciphering the LRRK code: LRRK1 and LRRK2 phosphorylate distinct Rab proteins and are regulated by diverse mechanisms.The Biochemical journal · 2021Article
- Pathogenic LRRK2 requires secondary factors to induce cellular toxicity.Bioscience reports · 2020Article
- LRRK2 Phosphorylation, More Than an Epiphenomenon.Frontiers in neuroscience · 2020Review
- Proteomics; applications in familial Parkinson's disease.Journal of neurochemistry · 2019Review
- RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits.Human molecular genetics · 2019Article
- Article
- Physiological and pathological functions of LRRK2: implications from substrate proteins.Neuronal signaling · 2018Review
- Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins.Proteomics · 2018Article
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Authors and funding
16 authors at 5 institutions in 3 countries.
Funding
Abstract
Genetic studies show that LRRK2, and not its closest paralogue LRRK1, is linked to Parkinson's disease. To gain insight into the molecular and cellular basis of this discrepancy, we searched for LRRK1- and LRRK2-specific cellular processes by identifying their distinct interacting proteins. A protein microarray-based interaction screen was performed with recombinant 3xFlag-LRRK1 and 3xFlag-LRRK2 and, in parallel, co-immunoprecipitation followed by mass spectrometry was performed from SH-SY5Y neuroblastoma cell lines stably expressing 3xFlag-LRRK1 or 3xFlag-LRRK2. We identified a set of LRRK1- and LRRK2-specific as well as common interactors. One of our most prominent findings was that both screens pointed to epidermal growth factor receptor (EGF-R) as a LRRK1-specific interactor, while 14-3-3 proteins were LRRK2-specific. This is consistent with phosphosite mapping of LRRK1, revealing phosphosites outside of 14-3-3 consensus binding motifs. To assess the functional relevance of these interactions, SH-SY5Y-LRRK1 and -LRRK2 cell lines were treated with LRRK2 kinase inhibitors that disrupt 14-3-3 binding, or with EGF, an EGF-R agonist. Redistribution of LRRK2, not LRRK1, from diffuse cytoplasmic to filamentous aggregates was observed after inhibitor treatment. Similarly, EGF induced translocation of LRRK1, but not of LRRK2, to endosomes. Our study confirms that LRRK1 and LRRK2 can carry out distinct functions by interacting with different cellular proteins. LRRK1 and LRRK2 (leucine-rich repeat kinase) interaction partners were identified by two different protein-protein interaction screens. These confirmed epidermal growth factor receptor (EGR-R) as a LRRK1-specific interactor, while 14-3-3 proteins were LRRK2-specific. Functional analysis of these interactions and the pathways they mediate shows that LRRK1 and LRRK2 signaling do not intersect, reflective of the differential role of both LRRKs in Parkinson's disease.
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