ArticleThe Biochemical journal2021
Deciphering the LRRK code: LRRK1 and LRRK2 phosphorylate distinct Rab proteins and are regulated by diverse mechanisms.
Article in The Biochemical journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 51 citations in OpenAlex.
- LRRK2: Molecular Mechanisms in Parkinson's Disease.International journal of molecular sciences · 2026Review
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- TBK1 activity regulates the directionality of axonal transport of signalling endosomes.Life science alliance · 2026Article
- Beyond resorption: targeting osteoclast fusion and polarization to restore balanced bone remodeling.Frontiers in pharmacology · 2026Review
- Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks.Cell reports · 2025Article
- Dynein-Dependent Endo-Lysosomal Degradation Drives Lewy Body Disorders Accompanied by Aβ Pathology.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Selectivity profiles and substrate recognition of Rab-phosphorylating kinases.The Biochemical journal · 2025Article
- The bridge-like lipid transport protein VPS13C/PARK23 mediates ER-lysosome contacts following lysosome damage.Nature cell biology · 2025Article
- CSN-CRL Complexes: New Regulators of Adipogenesis.Biomolecules · 2025Review
- Roles of LRRK2 and its orthologs in protecting against neurodegeneration and neurodevelopmental defects.Frontiers in cell and developmental biology · 2025Article
- Phosphorylation-driven effector switching of Rab7 and Rab12 by the leucine-rich repeat kinase 1 in mast cells.Frontiers in immunology · 2025Article
- Phosphorylation on serine 72 modulates Rab7A palmitoylation and retromer recruitment.Journal of cell science · 2025Article
- 14-3-3 phosphorylation inhibits 14-3-3θ's ability to regulate LRRK2 kinase activity and toxicity.Human molecular genetics · 2024Article
- LRRK2 kinase activity is necessary for development and regeneration in Nematostella vectensis.Neural development · 2024Article
- A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy.The Journal of cell biology · 2024Article
- LRRK2 kinase activity is necessary for development and regeneration in Nematostella vectensis.Research square · 2023Article
- Structure of LRRK1 and mechanisms of autoinhibition and activation.Nature structural & molecular biology · 2023Article
- Genome-wide screen reveals Rab12 GTPase as a critical activator of Parkinson's disease-linked LRRK2 kinase.eLife · 2023Article
- ArfGAP1 regulates the endosomal sorting of guidance receptors to promote directed collective cell migrationiScience · 2023Article
- Inhibition of the Exocyst Complex Attenuates the LRRK2 Pathological Effects.International journal of molecular sciences · 2023Article
Corrections and comments
- Erratum issued
Authors and funding
17 authors at 3 institutions in 3 countries.
Funding
Abstract
Autosomal dominant mutations in LRRK2 that enhance kinase activity cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases including Rab8A and Rab10 within its effector binding motif. Here, we explore whether LRRK1, a less studied homolog of LRRK2 that regulates growth factor receptor trafficking and osteoclast biology might also phosphorylate Rab proteins. Using mass spectrometry, we found that in LRRK1 knock-out cells, phosphorylation of Rab7A at Ser72 was most impacted. This residue lies at the equivalent site targeted by LRRK2 on Rab8A and Rab10. Accordingly, recombinant LRRK1 efficiently phosphorylated Rab7A at Ser72, but not Rab8A or Rab10. Employing a novel phospho-specific antibody, we found that phorbol ester stimulation of mouse embryonic fibroblasts markedly enhanced phosphorylation of Rab7A at Ser72 via LRRK1. We identify two LRRK1 mutations (K746G and I1412T), equivalent to the LRRK2 R1441G and I2020T Parkinson's mutations, that enhance LRRK1 mediated phosphorylation of Rab7A. We demonstrate that two regulators of LRRK2 namely Rab29 and VPS35[D620N], do not influence LRRK1. Widely used LRRK2 inhibitors do not inhibit LRRK1, but we identify a promiscuous inhibitor termed GZD-824 that inhibits both LRRK1 and LRRK2. The PPM1H Rab phosphatase when overexpressed dephosphorylates Rab7A. Finally, the interaction of Rab7A with its effector RILP is not affected by LRRK1 phosphorylation and we observe that maximal stimulation of the TBK1 or PINK1 pathway does not elevate Rab7A phosphorylation. Altogether, these findings reinforce the idea that the LRRK enzymes have evolved as major regulators of Rab biology with distinct substrate specificity.
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