{"gene":"LRRK1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2005,"finding":"LRRK1 is both a functional protein kinase and a GDP/GTP-binding protein; GTP binding to the Roc domain specifically stimulates LRRK1 kinase activity, proposing a model in which LRRK1 cycles between GTP-bound active and GDP-bound inactive states.","method":"In vitro kinase assay, GDP/GTP binding assay, Roc domain mutagenesis, and introduction of LRRK2 Parkinson's-equivalent mutations that downregulate LRRK1 kinase activity","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro biochemical assays (kinase and GTP binding) with mutagenesis in a single rigorous study","pmids":["16243488"],"is_preprint":false},{"year":2011,"finding":"LRRK1 forms a complex with activated EGFR via Grb2, is co-internalized with EGF into early endosomes, regulates EGFR transport from early to late endosomes in a kinase-dependent manner, and serves as a scaffold facilitating EGFR interaction with the ESCRT-0 complex for sorting into multivesicular body intraluminal vesicles.","method":"Co-immunoprecipitation, fluorescence microscopy/co-localization, RNAi knockdown with EGFR trafficking readout, kinase-dead mutant rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, live-cell imaging, kinase-dead mutants, and multiple orthogonal functional assays; subsequently replicated and extended by multiple independent studies","pmids":["21245839"],"is_preprint":false},{"year":2012,"finding":"EGFR phosphorylates LRRK1 at Tyr-944, reducing LRRK1 kinase activity; mutation Y944F abolishes this phosphorylation, causing hyperactivation of LRRK1, enhanced endosome motility toward the perinuclear region, and defective multivesicular body formation — establishing a feedback loop where EGFR downregulates LRRK1 during endosomal trafficking.","method":"Site-directed mutagenesis (Y944F), in vitro kinase assay, phospho-specific detection, fluorescence microscopy of endosome motility, dominant-negative and rescue experiments","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with in vitro kinase assay and functional cellular readouts in a single focused study","pmids":["22337768"],"is_preprint":false},{"year":2014,"finding":"LRRK1 phosphorylates CLIP-170 at Thr1384 in its C-terminal zinc knuckle motif, promoting CLIP-170 association with dynein-dynactin complexes and accumulation of p150Glued at microtubule plus ends, thereby facilitating migration of EGFR-containing endosomes.","method":"In vitro kinase assay identifying CLIP-170 as LRRK1 substrate, phospho-specific antibody, Co-IP, fluorescence microscopy of endosome movement, RNAi knockdown","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro substrate phosphorylation with mutagenesis and functional cellular readout in one study","pmids":["25413345"],"is_preprint":false},{"year":2014,"finding":"EGFR is a LRRK1-specific interactor (not LRRK2), while 14-3-3 proteins are LRRK2-specific; EGF stimulation induces translocation of LRRK1 (but not LRRK2) to endosomes, confirming distinct cellular functions; phosphosite mapping of LRRK1 reveals phosphosites outside 14-3-3 consensus binding motifs.","method":"Protein microarray-based interaction screen, co-immunoprecipitation followed by mass spectrometry, stable cell lines expressing 3xFlag-LRRK1 or LRRK2, EGF-induced translocation imaging","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent parallel screens (microarray + Co-IP/MS) plus functional localization assay; confirms findings from PMID:21245839","pmids":["24947832"],"is_preprint":false},{"year":2015,"finding":"LRRK1 is a PLK1 substrate phosphorylated at Ser1790; PLK1 phosphorylation enables CDK1-mediated activation of LRRK1 at centrosomes; activated LRRK1 phosphorylates CDK5RAP2 at Ser140 in its γ-tubulin-binding motif, promoting CDK5RAP2–γ-tubulin interaction and astral microtubule nucleation to regulate mitotic spindle orientation.","method":"In vitro kinase assay (PLK1→LRRK1, LRRK1→CDK5RAP2), phospho-specific antibodies, centrosome fractionation, spindle orientation microscopy, RNAi knockdown and rescue with phosphomimetic/phospho-dead mutants","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of kinase cascade in vitro with mutagenesis and clear cellular phenotypic readout; multiple orthogonal methods in one rigorous study","pmids":["26192437"],"is_preprint":false},{"year":2017,"finding":"Full-length LRRK1 forms a homodimer with two-fold symmetry, structurally similar to the LRRK2 dimer; cryo-EM at 25 Å resolution reveals overall dimeric architecture, suggesting dimerization mechanisms are conserved between LRRK1 and LRRK2.","method":"Cryo-electron microscopy and single particle analysis of purified full-length LRRK1 protein","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — cryo-EM structure at low resolution (25 Å) in a single study; limited functional validation of dimerization consequences","pmids":["28819229"],"is_preprint":false},{"year":2018,"finding":"LRRK1 binds the Longin domain of VAMP7 and negatively regulates VAMP7-mediated lysosomal exocytosis; LRRK1 and VARP compete for VAMP7 binding in a tug-of-war mechanism that controls the peripheral pool of secretory lysosomes and cellular response to substrate rigidity.","method":"Co-immunoprecipitation (LRRK1-VAMP7 interaction), VAMP7 knockdown/rescue with Longin domain mutants, atomic force microscopy for substrate rigidity, secretion assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional secretion assay in a single lab with multiple readouts","pmids":["30240735"],"is_preprint":false},{"year":2018,"finding":"LRRK1 phosphorylates L-plastin at Ser5 in osteoclasts; Lrrk1-deficient osteoclasts lack L-plastin Ser5 phosphorylation; L-plastin knockout mice show increased trabecular bone volume, linking LRRK1-mediated L-plastin phosphorylation to actin assembly and osteoclast function.","method":"Metal affinity purification coupled LC/MS of phosphoproteins from wild-type vs Lrrk1-KO osteoclasts, phospho-specific western blotting, micro-CT of L-plastin KO mice","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry phosphoproteomics confirmed by phospho-specific antibody plus in vivo KO phenotype; single lab","pmids":["30136304"],"is_preprint":false},{"year":2019,"finding":"LRRK1 phosphorylates GTP-bound Rab7 at Ser72 at the endosomal membrane; this phosphorylation promotes Rab7 interaction with its effector RILP, leading to dynein-dynactin recruitment to Rab7-positive vesicles and dynein-driven transport of EGFR-containing endosomes toward the perinuclear region.","method":"In vitro kinase assay (LRRK1 + Rab7), phospho-Rab7 S72 antibody, Co-IP of RILP with phospho-Rab7, fluorescence microscopy of endosome motility, dominant-negative and RNAi experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro substrate phosphorylation combined with interaction studies and functional endosome transport readout; independently replicated by PMID:33459343","pmids":["31085713"],"is_preprint":false},{"year":2010,"finding":"LRRK1 and LRRK2 physically interact and form heterodimers, as demonstrated by co-immunoprecipitation.","method":"Co-immunoprecipitation of LRRK1-LRRK2 heterodimer in transfected cells","journal":"Mechanisms of ageing and development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment, single lab, limited mechanistic follow-up","pmids":["20144646"],"is_preprint":false},{"year":2016,"finding":"Biallelic loss-of-function mutations in LRRK1 cause osteosclerotic metaphyseal dysplasia in humans; in vitro functional studies using osteoclasts from Lrrk1-deficient mice confirmed that the human deletion is a loss-of-function mutation, establishing LRRK1 as essential for osteoclast-mediated bone resorption and bone mass regulation.","method":"Whole-exome sequencing to identify mutation, in vitro osteoclast functional assay from Lrrk1-KO mice, comparison with Lrrk1-deficient mouse skeletal phenotype","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics corroborated by in vitro osteoclast functional assay; replicated across multiple independent OSMD cases with LRRK1 mutations","pmids":["27055475"],"is_preprint":false},{"year":2016,"finding":"LRRK1 is required for BCR-mediated NF-κB activation; Lrrk1-deficient mice have impaired B-cell proliferation, survival, IgG3 class-switch recombination, and NF-κB target gene expression; LRRK1 physically interacts with CARMA1 and potently synergizes with it to enhance NF-κB activation.","method":"Lrrk1 knockout mouse model, BCR stimulation assays, NF-κB reporter and target gene expression, Co-immunoprecipitation of LRRK1-CARMA1, B-cell differentiation and immunoglobulin production assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined cellular phenotype plus Co-IP establishing physical interaction with CARMA1; multiple orthogonal readouts","pmids":["27166870"],"is_preprint":false},{"year":2020,"finding":"A LRRK1 splice-site mutation causing loss of kinase function results in strongly reduced phosphorylation of L-plastin at Ser5 in patient-derived osteoclasts, which show markedly abnormal morphology and impaired bone resorption (superficial erosion only, no resorption pits), directly linking LRRK1 kinase activity to osteoclast actin cytoskeleton function in humans.","method":"Patient-derived osteoclast differentiation from peripheral blood monocytes, phospho-L-plastin Ser5 western blot, bone resorption pit assay, cDNA sequencing of splice mutation","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived cells with defined mutation, phosphorylation readout, and functional bone resorption assay; corroborates PMID:30136304","pmids":["32119750"],"is_preprint":false},{"year":2021,"finding":"LRRK1 specifically phosphorylates Rab7A at Ser72 (but not Rab8A or Rab10); phorbol ester stimulation of mouse embryonic fibroblasts markedly enhances Rab7A Ser72 phosphorylation via LRRK1; LRRK1 mutations equivalent to LRRK2 Parkinson's mutations (K746G and I1412T) enhance LRRK1-mediated Rab7A phosphorylation; Rab29 and VPS35[D620N] do not regulate LRRK1 (unlike LRRK2); PPM1H phosphatase dephosphorylates phospho-Rab7A; LRRK1 phosphorylation of Rab7A does not affect its interaction with effector RILP.","method":"Mass spectrometry of LRRK1-KO vs wild-type cells, recombinant LRRK1 in vitro kinase assay with multiple Rab substrates, phospho-specific antibody, phorbol ester stimulation, LRRK2 inhibitor panel, GZD-824 inhibitor characterization","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (MS, in vitro kinase, phospho-antibody, cell-based stimulation, inhibitor profiling) in one comprehensive study; substrate specificity independently confirmed by PMID:31085713","pmids":["33459343"],"is_preprint":false},{"year":2022,"finding":"Multiple PKC isoforms phosphorylate and activate LRRK1 by phosphorylating Ser1064, Ser1074, and Thr1075 in the CORB GTPase domain (not the kinase domain); Thr1075 mutation to Ala blocks PKC-mediated activation; phosphomimetic triple Glu mutation enhances LRRK1 kinase activity ~3-fold; PKC inhibitors including darovasertib block LRRK1 activation in HEK293 cells.","method":"In vitro kinase assay (multiple PKC isoforms + recombinant LRRK1), phosphatase reversal, site-directed mutagenesis (Ala and Glu substitutions), cell-based kinase activity assay with PKC inhibitors","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with multiple PKC isoforms, mutagenesis of activation sites, and cell-based validation; multiple orthogonal methods in one rigorous study","pmids":["36040231"],"is_preprint":false},{"year":2022,"finding":"LRRK1 functions downstream of ULK1/ULK2 in Parkin-mediated mitophagy; the ULK complex recruits LRRK1 to mitochondria via ATG13 interaction; LRRK1 phosphorylates Rab7 Ser72 at mitochondria to initiate mitophagosome formation; ectopic targeting of active LRRK1 to mitochondria is sufficient to induce Rab7 Ser72 phosphorylation and bypass ATG13 requirement.","method":"Genetic epistasis (ULK1/ULK2 KO, ATG13 KO), mitophagy assays, ectopic LRRK1 mitochondrial targeting construct, phospho-Rab7 S72 detection, Co-IP of LRRK1 with ATG13","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis combined with ectopic-targeting rescue and Co-IP; pathway position clearly defined with multiple orthogonal approaches","pmids":["36408770"],"is_preprint":false},{"year":2022,"finding":"LRRK1 phosphorylates NDEL1 at Ser155; this phosphorylation promotes NDEL1 interaction with intermediate chains of cytoplasmic dynein-2 and drives cilia disassembly via retrograde intraflagellar transport; PLK1 phosphorylates and activates LRRK1 at the cilia base during serum-induced ciliary resorption, defining a PLK1-LRRK1-NDEL1 pathway in cilia disassembly.","method":"RNAi depletion of LRRK1 with cilia resorption assay, in vitro kinase assay (LRRK1→NDEL1 Ser155), phospho-specific detection, Co-IP of NDEL1 with dynein-2 intermediate chains, PLK1 inhibitor experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro substrate phosphorylation with mutagenesis, Co-IP of downstream complex, and clear functional cilia resorption phenotype; extends established PLK1-LRRK1 pathway from PMID:26192437","pmids":["36254578"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of monomeric and dimeric LRRK1 show that, unlike LRRK2 (which is sterically autoinhibited as a monomer), LRRK1 is autoinhibited in a dimer-dependent manner and has an additional level of autoinhibition absent in LRRK2 that prevents kinase activation.","method":"Cryo-EM structure determination of monomeric and dimeric full-length LRRK1, structural comparison with LRRK2 cryo-EM structures, evolutionary analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures of both monomer and dimer forms with detailed mechanistic interpretation; published in high-tier structural journal","pmids":["37857821"],"is_preprint":false},{"year":2023,"finding":"LRRK1 acts as a scaffold at ER-endosome contact sites to facilitate PTP1B-mediated dephosphorylation of EGFR (at pY944 on LRRK1 and on EGFR itself); LRRK1 is required for the PTP1B-EGFR interaction in response to EGF; PTP1B in turn reactivates LRRK1 by dephosphorylating pY944, promoting EGFR-endosome transport to the perinuclear region; this establishes the ER-endosome contact site as a hub for LRRK1-dependent EGFR trafficking regulation.","method":"Co-immunoprecipitation (PTP1B-EGFR-LRRK1), proximity ligation assay at ER-endosome contact sites, phospho-specific antibodies, LRRK1 knockdown with rescue experiments, live-cell imaging of endosome motility","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, proximity ligation, and functional trafficking assays; multiple orthogonal methods; builds on established LRRK1-EGFR pathway","pmids":["36744428"],"is_preprint":false},{"year":2014,"finding":"FIH-1 (HIF1AN) binds LRRK1 and disrupts the EGFR/LRRK1 complex; this prevents proper EGFR turnover and enhances EGFR signaling through the MAPK pathway to promote keratinocyte migration.","method":"Co-immunoprecipitation (FIH-1/LRRK1 interaction), in vitro scratch wound assay, EGFR signaling readouts (ERK1/2 phosphorylation), FIH-1 null mouse wound healing phenotype","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional migration assay in a single lab with in vivo KO confirmation, but mechanistic detail of the disruption is limited","pmids":["25455687"],"is_preprint":false},{"year":2025,"finding":"LRRK1 phosphorylates Rab43 (a novel LRRK1:Rab43 kinase pair identified in vitro); comprehensive substrate profiling shows LRRK1 and LRRK2 phosphorylate distinct sets of Rab GTPases.","method":"In vitro kinase profiling of recombinant LRRK1 against a panel of Rab GTPases, mass spectrometry-based phosphorylation profiling","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay in a preprint, single study, no cellular validation of Rab43 phosphorylation by LRRK1 reported","pmids":[],"is_preprint":true}],"current_model":"LRRK1 is a GTPase-regulated, multi-domain serine/threonine kinase whose activity is stimulated by GTP binding to its Roc domain, activated by PKC phosphorylation of CORB domain residues (Ser1064/Ser1074/Thr1075) and by PLK1 phosphorylation (Ser1790), and negatively regulated by EGFR-mediated phosphorylation at Tyr944; its principal established substrates are Rab7A (Ser72, driving dynein-dependent endosomal transport and mitophagy), CDK5RAP2 (Ser140, regulating centrosomal microtubule nucleation and mitotic spindle orientation), CLIP-170 (Thr1384, promoting dynactin recruitment for endosome movement), NDEL1 (Ser155, driving cilia disassembly via dynein-2), and L-plastin (Ser5, regulating osteoclast actin assembly); structurally, LRRK1 is autoinhibited in a unique dimer-dependent manner distinct from LRRK2; it functions as a scaffold at ER-endosome contact sites to coordinate EGFR dephosphorylation by PTP1B, interacts with CARMA1 to activate NF-κB in B cells, and loss-of-function mutations cause osteosclerotic metaphyseal dysplasia due to defective osteoclast bone resorption."},"narrative":{"mechanistic_narrative":"LRRK1 is a multi-domain serine/threonine kinase that operates at the intersection of endosomal trafficking, cytoskeletal regulation, and bone homeostasis, and whose catalytic output is gated by both GTP binding and a network of upstream phosphorylation events [PMID:16243488, PMID:31085713, PMID:26192437]. GTP binding to its Roc domain stimulates kinase activity, defining a GTP/GDP cycle that switches the enzyme between active and inactive states [PMID:16243488]. Activity is further tuned by upstream kinases: PKC isoforms phosphorylate Ser1064/Ser1074/Thr1075 in the CORB GTPase domain to activate LRRK1 [PMID:36040231], PLK1 phosphorylates Ser1790 to enable CDK1-dependent activation at centrosomes and at the cilia base [PMID:26192437, PMID:36254578], and EGFR phosphorylates Tyr944 to suppress activity, forming a feedback loop during endosomal trafficking that is relieved by PTP1B-mediated dephosphorylation at ER-endosome contact sites [PMID:22337768, PMID:36744428]. Structurally, LRRK1 is autoinhibited in a dimer-dependent manner distinct from the monomeric autoinhibition of LRRK2 [PMID:37857821]. A principal substrate is Rab7A, phosphorylated at Ser72, which couples LRRK1 to dynein-dynactin-driven perinuclear transport of EGFR-containing endosomes and to ULK1/ULK2-dependent Parkin-mediated mitophagy [PMID:31085713, PMID:36408770]. Through additional substrates LRRK1 controls microtubule-based processes—CDK5RAP2 (Ser140) for centrosomal microtubule nucleation and spindle orientation [PMID:26192437], CLIP-170 (Thr1384) for dynactin recruitment to migrating endosomes [PMID:25413345], and NDEL1 (Ser155) for dynein-2-dependent cilia disassembly [PMID:36254578]. In osteoclasts LRRK1 phosphorylates L-plastin at Ser5 to regulate the actin cytoskeleton, and biallelic loss-of-function LRRK1 mutations cause osteosclerotic metaphyseal dysplasia through defective osteoclast bone resorption [PMID:30136304, PMID:27055475, PMID:32119750]. LRRK1 also functions as a scaffold rather than purely as a kinase, recruiting EGFR to ESCRT-0 machinery for multivesicular body sorting and synergizing with CARMA1 to drive BCR-induced NF-κB activation in B cells [PMID:21245839, PMID:27166870].","teleology":[{"year":2005,"claim":"Established LRRK1 as a bona fide kinase whose activity is controlled by an intramolecular GTPase switch, framing it as a GTP-regulated enzyme rather than a passive scaffold.","evidence":"In vitro kinase and GDP/GTP binding assays with Roc-domain mutagenesis and Parkinson's-equivalent mutations","pmids":["16243488"],"confidence":"High","gaps":["Did not identify physiological substrates","GTP/GDP cycle dynamics in cells not measured","No structural basis for Roc-to-kinase coupling"]},{"year":2011,"claim":"Defined LRRK1's first cellular role: a kinase-dependent regulator and scaffold for EGFR transit through the endosomal system toward multivesicular bodies.","evidence":"Co-IP via Grb2, co-internalization imaging, RNAi with EGFR trafficking readout, and kinase-dead rescue","pmids":["21245839"],"confidence":"High","gaps":["Endosomal substrate of LRRK1 not yet identified","Mechanism of ESCRT-0 facilitation unresolved"]},{"year":2012,"claim":"Revealed a feedback loop in which EGFR phosphorylates LRRK1 at Tyr944 to dampen its activity, coupling receptor signaling to control of endosome motility.","evidence":"Y944F mutagenesis, in vitro kinase assay, phospho-detection, and endosome motility imaging","pmids":["22337768"],"confidence":"High","gaps":["Phosphatase reversing pY944 not identified at this stage","Structural effect of pY944 on kinase domain unknown"]},{"year":2014,"claim":"Distinguished LRRK1 from its paralog LRRK2 by partner specificity (EGFR vs 14-3-3) and identified CLIP-170 as a substrate linking LRRK1 to dynein/dynactin-driven endosome migration.","evidence":"Protein microarray and Co-IP/MS interaction screens, EGF-induced translocation imaging, and in vitro CLIP-170 phosphorylation with functional readout","pmids":["24947832","25413345"],"confidence":"High","gaps":["How pTyr944 and CLIP-170 phosphorylation are temporally coordinated unclear","Direct dynactin-CLIP-170 stoichiometry not resolved"]},{"year":2014,"claim":"Showed LRRK1 activity can be modulated by FIH-1 disruption of the EGFR/LRRK1 complex, linking it to EGFR turnover and keratinocyte migration.","evidence":"Co-IP, scratch-wound migration assay, ERK readouts, and FIH-1 null wound-healing phenotype","pmids":["25455687"],"confidence":"Medium","gaps":["Molecular detail of how FIH-1 displaces the complex limited","Whether LRRK1 kinase activity changes upon FIH-1 binding not tested"]},{"year":2015,"claim":"Placed LRRK1 in a mitotic kinase cascade: PLK1/CDK1 activate it at centrosomes, and it phosphorylates CDK5RAP2 to control microtubule nucleation and spindle orientation.","evidence":"Reconstituted in vitro kinase cascade, phospho-antibodies, centrosome fractionation, and spindle-orientation phenotypes with mutant rescue","pmids":["26192437"],"confidence":"High","gaps":["Roc/GTP contribution to centrosomal activation not dissected","Whether the same activation applies outside mitosis unknown"]},{"year":2016,"claim":"Connected LRRK1 to human disease and to immune signaling: loss-of-function causes osteosclerotic metaphyseal dysplasia via defective osteoclast resorption, and LRRK1 synergizes with CARMA1 to drive BCR-induced NF-κB.","evidence":"Whole-exome sequencing plus Lrrk1-KO osteoclast assays; Lrrk1-KO mouse B-cell phenotyping with LRRK1-CARMA1 Co-IP","pmids":["27055475","27166870"],"confidence":"High","gaps":["Osteoclast substrate not identified in 2016","Mechanism of CARMA1 synergy and whether it is kinase-dependent unresolved"]},{"year":2017,"claim":"Provided the first architectural view, showing LRRK1 forms a two-fold symmetric homodimer broadly resembling the LRRK2 dimer.","evidence":"Low-resolution (25 Å) cryo-EM single-particle analysis of full-length LRRK1","pmids":["28819229"],"confidence":"Medium","gaps":["Resolution too low for domain-level mechanism","Autoinhibition not addressed","Functional consequences of dimerization not tested"]},{"year":2018,"claim":"Expanded LRRK1's substrate and interaction repertoire to osteoclast actin (L-plastin Ser5) and to lysosomal exocytosis control via VAMP7 binding.","evidence":"Phosphoproteomics of WT vs Lrrk1-KO osteoclasts with KO mouse micro-CT; LRRK1-VAMP7 Co-IP with secretion and rigidity assays","pmids":["30136304","30240735"],"confidence":"Medium","gaps":["VAMP7 regulation shown by a single lab without reciprocal validation","Direct kinase dependence of VAMP7 effect not established"]},{"year":2019,"claim":"Identified Rab7A Ser72 as a central LRRK1 substrate that recruits RILP and dynein-dynactin to drive perinuclear endosome transport, mechanistically unifying earlier trafficking observations.","evidence":"In vitro kinase assay, phospho-Rab7 S72 antibody, RILP Co-IP, and endosome motility imaging with dominant-negative/RNAi","pmids":["31085713"],"confidence":"High","gaps":["Reconciling RILP-promoting vs RILP-neutral effects of pRab7A across studies","In vivo relevance of Rab7 phosphorylation not yet defined"]},{"year":2020,"claim":"Demonstrated in patient-derived cells that LRRK1 kinase activity is required for L-plastin Ser5 phosphorylation and normal osteoclast resorption, directly tying the kinase to human bone disease.","evidence":"Patient osteoclasts with a kinase-disrupting splice mutation, phospho-L-plastin western blot, and bone resorption pit assays","pmids":["32119750"],"confidence":"High","gaps":["Whether other substrates contribute to the osteoclast defect not resolved","Mechanism linking L-plastin pSer5 to resorption pit formation incomplete"]},{"year":2021,"claim":"Defined LRRK1 substrate specificity and upstream regulation, showing it phosphorylates Rab7A (not Rab8A/Rab10), is activated by phorbol esters, is dephosphorylated by PPM1H, and is regulated independently of LRRK2's Rab29/VPS35 inputs.","evidence":"MS of LRRK1-KO vs WT cells, in vitro kinase profiling across Rab substrates, phorbol-ester stimulation, and inhibitor profiling","pmids":["33459343"],"confidence":"High","gaps":["Discrepancy with prior report on pRab7A-RILP coupling","Identity of the PKC-coupled upstream signal not pinned down here"]},{"year":2022,"claim":"Integrated LRRK1 into multiple Rab7-dependent and cytoskeletal pathways: ULK1/2-ATG13-recruited mitophagy, PLK1-driven NDEL1 Ser155 phosphorylation for cilia disassembly, and PKC-mediated CORB-domain activation.","evidence":"Genetic epistasis and ectopic mitochondrial targeting for mitophagy; in vitro NDEL1 phosphorylation with dynein-2 Co-IP and cilia resorption; PKC isoform reconstitution with activation-site mutagenesis","pmids":["36408770","36254578","36040231"],"confidence":"High","gaps":["How distinct activation cues (PKC, PLK1, ULK) select specific substrate outputs unclear","Spatial control restricting each substrate engagement not fully mapped"]},{"year":2023,"claim":"Resolved LRRK1's unique regulatory logic—dimer-dependent autoinhibition distinct from LRRK2—and placed EGFR/LRRK1 reactivation at ER-endosome contact sites via PTP1B.","evidence":"Cryo-EM of monomeric and dimeric LRRK1 with LRRK2 comparison; Co-IP, proximity ligation, and trafficking assays for the PTP1B-EGFR-LRRK1 axis","pmids":["37857821","36744428"],"confidence":"High","gaps":["How phosphorylation events relieve dimer autoinhibition structurally not shown","Dynamics of LRRK1 monomer-dimer transition in cells unmeasured"]},{"year":2025,"claim":"Began broadening the substrate landscape by proposing Rab43 as a new LRRK1 target distinct from LRRK2's Rab set.","evidence":"In vitro kinase profiling against a Rab panel with MS phosphorylation profiling (preprint)","pmids":[],"confidence":"Low","gaps":["No cellular validation of Rab43 phosphorylation by LRRK1","Preprint, not yet peer-reviewed","Physiological role of any Rab43 phosphorylation unknown"]},{"year":null,"claim":"How LRRK1's multiple upstream activation inputs (GTP, PKC, PLK1) are spatially and temporally coordinated to select among its diverse substrates across trafficking, mitosis, ciliogenesis, mitophagy, and bone remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking activation cue to substrate choice","Limited in vivo substrate-phosphorylation data outside osteoclasts","Structural mechanism coupling Roc/CORB phosphorylation to kinase activation not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,5,8,9,14,17]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,9,15]},{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,19]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2,4,9]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[16]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[17]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2,9,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,12,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12]}],"complexes":[],"partners":["RAB7A","EGFR","CDK5RAP2","CLIP-170","NDEL1","VAMP7","CARMA1","ATG13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q38SD2","full_name":"Leucine-rich repeat serine/threonine-protein kinase 1","aliases":[],"length_aa":2015,"mass_kda":225.4,"function":"Serine/threonine-protein kinase which phosphorylates RAB proteins involved in intracellular trafficking (PubMed:36040231). Phosphorylates RAB7A; this activity is dependent on protein kinase C (PKC) activation (PubMed:36040231, PubMed:37558661, PubMed:37857821). Plays a role in the negative regulation of bone mass, acting through the maturation of osteoclasts (By similarity)","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q38SD2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRRK1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRRK1","total_profiled":1310},"omim":[{"mim_id":"615198","title":"OSTEOSCLEROTIC METAPHYSEAL DYSPLASIA; OSMD","url":"https://www.omim.org/entry/615198"},{"mim_id":"612938","title":"GROWTH RETARDATION, DEVELOPMENTAL DELAY, AND FACIAL DYSMORPHISM; GDFD","url":"https://www.omim.org/entry/612938"},{"mim_id":"612460","title":"BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 14; BMIQ14","url":"https://www.omim.org/entry/612460"},{"mim_id":"610986","title":"LEUCINE-RICH REPEAT KINASE 1; LRRK1","url":"https://www.omim.org/entry/610986"},{"mim_id":"610966","title":"FTO ALPHA-KETOGLUTARATE-DEPENDENT DIOXYGENASE; FTO","url":"https://www.omim.org/entry/610966"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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mutagenesis, and introduction of LRRK2 Parkinson's-equivalent mutations that downregulate LRRK1 kinase activity\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro biochemical assays (kinase and GTP binding) with mutagenesis in a single rigorous study\",\n      \"pmids\": [\"16243488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LRRK1 forms a complex with activated EGFR via Grb2, is co-internalized with EGF into early endosomes, regulates EGFR transport from early to late endosomes in a kinase-dependent manner, and serves as a scaffold facilitating EGFR interaction with the ESCRT-0 complex for sorting into multivesicular body intraluminal vesicles.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy/co-localization, RNAi knockdown with EGFR trafficking readout, kinase-dead mutant rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, live-cell imaging, kinase-dead mutants, and multiple orthogonal functional assays; subsequently replicated and extended by multiple independent studies\",\n      \"pmids\": [\"21245839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EGFR phosphorylates LRRK1 at Tyr-944, reducing LRRK1 kinase activity; mutation Y944F abolishes this phosphorylation, causing hyperactivation of LRRK1, enhanced endosome motility toward the perinuclear region, and defective multivesicular body formation — establishing a feedback loop where EGFR downregulates LRRK1 during endosomal trafficking.\",\n      \"method\": \"Site-directed mutagenesis (Y944F), in vitro kinase assay, phospho-specific detection, fluorescence microscopy of endosome motility, dominant-negative and rescue experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with in vitro kinase assay and functional cellular readouts in a single focused study\",\n      \"pmids\": [\"22337768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LRRK1 phosphorylates CLIP-170 at Thr1384 in its C-terminal zinc knuckle motif, promoting CLIP-170 association with dynein-dynactin complexes and accumulation of p150Glued at microtubule plus ends, thereby facilitating migration of EGFR-containing endosomes.\",\n      \"method\": \"In vitro kinase assay identifying CLIP-170 as LRRK1 substrate, phospho-specific antibody, Co-IP, fluorescence microscopy of endosome movement, RNAi knockdown\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro substrate phosphorylation with mutagenesis and functional cellular readout in one study\",\n      \"pmids\": [\"25413345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EGFR is a LRRK1-specific interactor (not LRRK2), while 14-3-3 proteins are LRRK2-specific; EGF stimulation induces translocation of LRRK1 (but not LRRK2) to endosomes, confirming distinct cellular functions; phosphosite mapping of LRRK1 reveals phosphosites outside 14-3-3 consensus binding motifs.\",\n      \"method\": \"Protein microarray-based interaction screen, co-immunoprecipitation followed by mass spectrometry, stable cell lines expressing 3xFlag-LRRK1 or LRRK2, EGF-induced translocation imaging\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent parallel screens (microarray + Co-IP/MS) plus functional localization assay; confirms findings from PMID:21245839\",\n      \"pmids\": [\"24947832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LRRK1 is a PLK1 substrate phosphorylated at Ser1790; PLK1 phosphorylation enables CDK1-mediated activation of LRRK1 at centrosomes; activated LRRK1 phosphorylates CDK5RAP2 at Ser140 in its γ-tubulin-binding motif, promoting CDK5RAP2–γ-tubulin interaction and astral microtubule nucleation to regulate mitotic spindle orientation.\",\n      \"method\": \"In vitro kinase assay (PLK1→LRRK1, LRRK1→CDK5RAP2), phospho-specific antibodies, centrosome fractionation, spindle orientation microscopy, RNAi knockdown and rescue with phosphomimetic/phospho-dead mutants\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of kinase cascade in vitro with mutagenesis and clear cellular phenotypic readout; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"26192437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Full-length LRRK1 forms a homodimer with two-fold symmetry, structurally similar to the LRRK2 dimer; cryo-EM at 25 Å resolution reveals overall dimeric architecture, suggesting dimerization mechanisms are conserved between LRRK1 and LRRK2.\",\n      \"method\": \"Cryo-electron microscopy and single particle analysis of purified full-length LRRK1 protein\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — cryo-EM structure at low resolution (25 Å) in a single study; limited functional validation of dimerization consequences\",\n      \"pmids\": [\"28819229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LRRK1 binds the Longin domain of VAMP7 and negatively regulates VAMP7-mediated lysosomal exocytosis; LRRK1 and VARP compete for VAMP7 binding in a tug-of-war mechanism that controls the peripheral pool of secretory lysosomes and cellular response to substrate rigidity.\",\n      \"method\": \"Co-immunoprecipitation (LRRK1-VAMP7 interaction), VAMP7 knockdown/rescue with Longin domain mutants, atomic force microscopy for substrate rigidity, secretion assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional secretion assay in a single lab with multiple readouts\",\n      \"pmids\": [\"30240735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LRRK1 phosphorylates L-plastin at Ser5 in osteoclasts; Lrrk1-deficient osteoclasts lack L-plastin Ser5 phosphorylation; L-plastin knockout mice show increased trabecular bone volume, linking LRRK1-mediated L-plastin phosphorylation to actin assembly and osteoclast function.\",\n      \"method\": \"Metal affinity purification coupled LC/MS of phosphoproteins from wild-type vs Lrrk1-KO osteoclasts, phospho-specific western blotting, micro-CT of L-plastin KO mice\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry phosphoproteomics confirmed by phospho-specific antibody plus in vivo KO phenotype; single lab\",\n      \"pmids\": [\"30136304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LRRK1 phosphorylates GTP-bound Rab7 at Ser72 at the endosomal membrane; this phosphorylation promotes Rab7 interaction with its effector RILP, leading to dynein-dynactin recruitment to Rab7-positive vesicles and dynein-driven transport of EGFR-containing endosomes toward the perinuclear region.\",\n      \"method\": \"In vitro kinase assay (LRRK1 + Rab7), phospho-Rab7 S72 antibody, Co-IP of RILP with phospho-Rab7, fluorescence microscopy of endosome motility, dominant-negative and RNAi experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro substrate phosphorylation combined with interaction studies and functional endosome transport readout; independently replicated by PMID:33459343\",\n      \"pmids\": [\"31085713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LRRK1 and LRRK2 physically interact and form heterodimers, as demonstrated by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation of LRRK1-LRRK2 heterodimer in transfected cells\",\n      \"journal\": \"Mechanisms of ageing and development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"20144646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Biallelic loss-of-function mutations in LRRK1 cause osteosclerotic metaphyseal dysplasia in humans; in vitro functional studies using osteoclasts from Lrrk1-deficient mice confirmed that the human deletion is a loss-of-function mutation, establishing LRRK1 as essential for osteoclast-mediated bone resorption and bone mass regulation.\",\n      \"method\": \"Whole-exome sequencing to identify mutation, in vitro osteoclast functional assay from Lrrk1-KO mice, comparison with Lrrk1-deficient mouse skeletal phenotype\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics corroborated by in vitro osteoclast functional assay; replicated across multiple independent OSMD cases with LRRK1 mutations\",\n      \"pmids\": [\"27055475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LRRK1 is required for BCR-mediated NF-κB activation; Lrrk1-deficient mice have impaired B-cell proliferation, survival, IgG3 class-switch recombination, and NF-κB target gene expression; LRRK1 physically interacts with CARMA1 and potently synergizes with it to enhance NF-κB activation.\",\n      \"method\": \"Lrrk1 knockout mouse model, BCR stimulation assays, NF-κB reporter and target gene expression, Co-immunoprecipitation of LRRK1-CARMA1, B-cell differentiation and immunoglobulin production assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined cellular phenotype plus Co-IP establishing physical interaction with CARMA1; multiple orthogonal readouts\",\n      \"pmids\": [\"27166870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A LRRK1 splice-site mutation causing loss of kinase function results in strongly reduced phosphorylation of L-plastin at Ser5 in patient-derived osteoclasts, which show markedly abnormal morphology and impaired bone resorption (superficial erosion only, no resorption pits), directly linking LRRK1 kinase activity to osteoclast actin cytoskeleton function in humans.\",\n      \"method\": \"Patient-derived osteoclast differentiation from peripheral blood monocytes, phospho-L-plastin Ser5 western blot, bone resorption pit assay, cDNA sequencing of splice mutation\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived cells with defined mutation, phosphorylation readout, and functional bone resorption assay; corroborates PMID:30136304\",\n      \"pmids\": [\"32119750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LRRK1 specifically phosphorylates Rab7A at Ser72 (but not Rab8A or Rab10); phorbol ester stimulation of mouse embryonic fibroblasts markedly enhances Rab7A Ser72 phosphorylation via LRRK1; LRRK1 mutations equivalent to LRRK2 Parkinson's mutations (K746G and I1412T) enhance LRRK1-mediated Rab7A phosphorylation; Rab29 and VPS35[D620N] do not regulate LRRK1 (unlike LRRK2); PPM1H phosphatase dephosphorylates phospho-Rab7A; LRRK1 phosphorylation of Rab7A does not affect its interaction with effector RILP.\",\n      \"method\": \"Mass spectrometry of LRRK1-KO vs wild-type cells, recombinant LRRK1 in vitro kinase assay with multiple Rab substrates, phospho-specific antibody, phorbol ester stimulation, LRRK2 inhibitor panel, GZD-824 inhibitor characterization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (MS, in vitro kinase, phospho-antibody, cell-based stimulation, inhibitor profiling) in one comprehensive study; substrate specificity independently confirmed by PMID:31085713\",\n      \"pmids\": [\"33459343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Multiple PKC isoforms phosphorylate and activate LRRK1 by phosphorylating Ser1064, Ser1074, and Thr1075 in the CORB GTPase domain (not the kinase domain); Thr1075 mutation to Ala blocks PKC-mediated activation; phosphomimetic triple Glu mutation enhances LRRK1 kinase activity ~3-fold; PKC inhibitors including darovasertib block LRRK1 activation in HEK293 cells.\",\n      \"method\": \"In vitro kinase assay (multiple PKC isoforms + recombinant LRRK1), phosphatase reversal, site-directed mutagenesis (Ala and Glu substitutions), cell-based kinase activity assay with PKC inhibitors\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with multiple PKC isoforms, mutagenesis of activation sites, and cell-based validation; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"36040231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRRK1 functions downstream of ULK1/ULK2 in Parkin-mediated mitophagy; the ULK complex recruits LRRK1 to mitochondria via ATG13 interaction; LRRK1 phosphorylates Rab7 Ser72 at mitochondria to initiate mitophagosome formation; ectopic targeting of active LRRK1 to mitochondria is sufficient to induce Rab7 Ser72 phosphorylation and bypass ATG13 requirement.\",\n      \"method\": \"Genetic epistasis (ULK1/ULK2 KO, ATG13 KO), mitophagy assays, ectopic LRRK1 mitochondrial targeting construct, phospho-Rab7 S72 detection, Co-IP of LRRK1 with ATG13\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis combined with ectopic-targeting rescue and Co-IP; pathway position clearly defined with multiple orthogonal approaches\",\n      \"pmids\": [\"36408770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRRK1 phosphorylates NDEL1 at Ser155; this phosphorylation promotes NDEL1 interaction with intermediate chains of cytoplasmic dynein-2 and drives cilia disassembly via retrograde intraflagellar transport; PLK1 phosphorylates and activates LRRK1 at the cilia base during serum-induced ciliary resorption, defining a PLK1-LRRK1-NDEL1 pathway in cilia disassembly.\",\n      \"method\": \"RNAi depletion of LRRK1 with cilia resorption assay, in vitro kinase assay (LRRK1→NDEL1 Ser155), phospho-specific detection, Co-IP of NDEL1 with dynein-2 intermediate chains, PLK1 inhibitor experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro substrate phosphorylation with mutagenesis, Co-IP of downstream complex, and clear functional cilia resorption phenotype; extends established PLK1-LRRK1 pathway from PMID:26192437\",\n      \"pmids\": [\"36254578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of monomeric and dimeric LRRK1 show that, unlike LRRK2 (which is sterically autoinhibited as a monomer), LRRK1 is autoinhibited in a dimer-dependent manner and has an additional level of autoinhibition absent in LRRK2 that prevents kinase activation.\",\n      \"method\": \"Cryo-EM structure determination of monomeric and dimeric full-length LRRK1, structural comparison with LRRK2 cryo-EM structures, evolutionary analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures of both monomer and dimer forms with detailed mechanistic interpretation; published in high-tier structural journal\",\n      \"pmids\": [\"37857821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LRRK1 acts as a scaffold at ER-endosome contact sites to facilitate PTP1B-mediated dephosphorylation of EGFR (at pY944 on LRRK1 and on EGFR itself); LRRK1 is required for the PTP1B-EGFR interaction in response to EGF; PTP1B in turn reactivates LRRK1 by dephosphorylating pY944, promoting EGFR-endosome transport to the perinuclear region; this establishes the ER-endosome contact site as a hub for LRRK1-dependent EGFR trafficking regulation.\",\n      \"method\": \"Co-immunoprecipitation (PTP1B-EGFR-LRRK1), proximity ligation assay at ER-endosome contact sites, phospho-specific antibodies, LRRK1 knockdown with rescue experiments, live-cell imaging of endosome motility\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, proximity ligation, and functional trafficking assays; multiple orthogonal methods; builds on established LRRK1-EGFR pathway\",\n      \"pmids\": [\"36744428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FIH-1 (HIF1AN) binds LRRK1 and disrupts the EGFR/LRRK1 complex; this prevents proper EGFR turnover and enhances EGFR signaling through the MAPK pathway to promote keratinocyte migration.\",\n      \"method\": \"Co-immunoprecipitation (FIH-1/LRRK1 interaction), in vitro scratch wound assay, EGFR signaling readouts (ERK1/2 phosphorylation), FIH-1 null mouse wound healing phenotype\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional migration assay in a single lab with in vivo KO confirmation, but mechanistic detail of the disruption is limited\",\n      \"pmids\": [\"25455687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRK1 phosphorylates Rab43 (a novel LRRK1:Rab43 kinase pair identified in vitro); comprehensive substrate profiling shows LRRK1 and LRRK2 phosphorylate distinct sets of Rab GTPases.\",\n      \"method\": \"In vitro kinase profiling of recombinant LRRK1 against a panel of Rab GTPases, mass spectrometry-based phosphorylation profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay in a preprint, single study, no cellular validation of Rab43 phosphorylation by LRRK1 reported\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LRRK1 is a GTPase-regulated, multi-domain serine/threonine kinase whose activity is stimulated by GTP binding to its Roc domain, activated by PKC phosphorylation of CORB domain residues (Ser1064/Ser1074/Thr1075) and by PLK1 phosphorylation (Ser1790), and negatively regulated by EGFR-mediated phosphorylation at Tyr944; its principal established substrates are Rab7A (Ser72, driving dynein-dependent endosomal transport and mitophagy), CDK5RAP2 (Ser140, regulating centrosomal microtubule nucleation and mitotic spindle orientation), CLIP-170 (Thr1384, promoting dynactin recruitment for endosome movement), NDEL1 (Ser155, driving cilia disassembly via dynein-2), and L-plastin (Ser5, regulating osteoclast actin assembly); structurally, LRRK1 is autoinhibited in a unique dimer-dependent manner distinct from LRRK2; it functions as a scaffold at ER-endosome contact sites to coordinate EGFR dephosphorylation by PTP1B, interacts with CARMA1 to activate NF-κB in B cells, and loss-of-function mutations cause osteosclerotic metaphyseal dysplasia due to defective osteoclast bone resorption.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRRK1 is a multi-domain serine/threonine kinase that operates at the intersection of endosomal trafficking, cytoskeletal regulation, and bone homeostasis, and whose catalytic output is gated by both GTP binding and a network of upstream phosphorylation events [#0, #9, #5]. GTP binding to its Roc domain stimulates kinase activity, defining a GTP/GDP cycle that switches the enzyme between active and inactive states [#0]. Activity is further tuned by upstream kinases: PKC isoforms phosphorylate Ser1064/Ser1074/Thr1075 in the CORB GTPase domain to activate LRRK1 [#15], PLK1 phosphorylates Ser1790 to enable CDK1-dependent activation at centrosomes and at the cilia base [#5, #17], and EGFR phosphorylates Tyr944 to suppress activity, forming a feedback loop during endosomal trafficking that is relieved by PTP1B-mediated dephosphorylation at ER-endosome contact sites [#2, #19]. Structurally, LRRK1 is autoinhibited in a dimer-dependent manner distinct from the monomeric autoinhibition of LRRK2 [#18]. A principal substrate is Rab7A, phosphorylated at Ser72, which couples LRRK1 to dynein-dynactin-driven perinuclear transport of EGFR-containing endosomes and to ULK1/ULK2-dependent Parkin-mediated mitophagy [#9, #16]. Through additional substrates LRRK1 controls microtubule-based processes—CDK5RAP2 (Ser140) for centrosomal microtubule nucleation and spindle orientation [#5], CLIP-170 (Thr1384) for dynactin recruitment to migrating endosomes [#3], and NDEL1 (Ser155) for dynein-2-dependent cilia disassembly [#17]. In osteoclasts LRRK1 phosphorylates L-plastin at Ser5 to regulate the actin cytoskeleton, and biallelic loss-of-function LRRK1 mutations cause osteosclerotic metaphyseal dysplasia through defective osteoclast bone resorption [#8, #11, #13]. LRRK1 also functions as a scaffold rather than purely as a kinase, recruiting EGFR to ESCRT-0 machinery for multivesicular body sorting and synergizing with CARMA1 to drive BCR-induced NF-κB activation in B cells [#1, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established LRRK1 as a bona fide kinase whose activity is controlled by an intramolecular GTPase switch, framing it as a GTP-regulated enzyme rather than a passive scaffold.\",\n      \"evidence\": \"In vitro kinase and GDP/GTP binding assays with Roc-domain mutagenesis and Parkinson's-equivalent mutations\",\n      \"pmids\": [\"16243488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify physiological substrates\", \"GTP/GDP cycle dynamics in cells not measured\", \"No structural basis for Roc-to-kinase coupling\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined LRRK1's first cellular role: a kinase-dependent regulator and scaffold for EGFR transit through the endosomal system toward multivesicular bodies.\",\n      \"evidence\": \"Co-IP via Grb2, co-internalization imaging, RNAi with EGFR trafficking readout, and kinase-dead rescue\",\n      \"pmids\": [\"21245839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endosomal substrate of LRRK1 not yet identified\", \"Mechanism of ESCRT-0 facilitation unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a feedback loop in which EGFR phosphorylates LRRK1 at Tyr944 to dampen its activity, coupling receptor signaling to control of endosome motility.\",\n      \"evidence\": \"Y944F mutagenesis, in vitro kinase assay, phospho-detection, and endosome motility imaging\",\n      \"pmids\": [\"22337768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase reversing pY944 not identified at this stage\", \"Structural effect of pY944 on kinase domain unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Distinguished LRRK1 from its paralog LRRK2 by partner specificity (EGFR vs 14-3-3) and identified CLIP-170 as a substrate linking LRRK1 to dynein/dynactin-driven endosome migration.\",\n      \"evidence\": \"Protein microarray and Co-IP/MS interaction screens, EGF-induced translocation imaging, and in vitro CLIP-170 phosphorylation with functional readout\",\n      \"pmids\": [\"24947832\", \"25413345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How pTyr944 and CLIP-170 phosphorylation are temporally coordinated unclear\", \"Direct dynactin-CLIP-170 stoichiometry not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed LRRK1 activity can be modulated by FIH-1 disruption of the EGFR/LRRK1 complex, linking it to EGFR turnover and keratinocyte migration.\",\n      \"evidence\": \"Co-IP, scratch-wound migration assay, ERK readouts, and FIH-1 null wound-healing phenotype\",\n      \"pmids\": [\"25455687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular detail of how FIH-1 displaces the complex limited\", \"Whether LRRK1 kinase activity changes upon FIH-1 binding not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed LRRK1 in a mitotic kinase cascade: PLK1/CDK1 activate it at centrosomes, and it phosphorylates CDK5RAP2 to control microtubule nucleation and spindle orientation.\",\n      \"evidence\": \"Reconstituted in vitro kinase cascade, phospho-antibodies, centrosome fractionation, and spindle-orientation phenotypes with mutant rescue\",\n      \"pmids\": [\"26192437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Roc/GTP contribution to centrosomal activation not dissected\", \"Whether the same activation applies outside mitosis unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected LRRK1 to human disease and to immune signaling: loss-of-function causes osteosclerotic metaphyseal dysplasia via defective osteoclast resorption, and LRRK1 synergizes with CARMA1 to drive BCR-induced NF-κB.\",\n      \"evidence\": \"Whole-exome sequencing plus Lrrk1-KO osteoclast assays; Lrrk1-KO mouse B-cell phenotyping with LRRK1-CARMA1 Co-IP\",\n      \"pmids\": [\"27055475\", \"27166870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Osteoclast substrate not identified in 2016\", \"Mechanism of CARMA1 synergy and whether it is kinase-dependent unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the first architectural view, showing LRRK1 forms a two-fold symmetric homodimer broadly resembling the LRRK2 dimer.\",\n      \"evidence\": \"Low-resolution (25 Å) cryo-EM single-particle analysis of full-length LRRK1\",\n      \"pmids\": [\"28819229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Resolution too low for domain-level mechanism\", \"Autoinhibition not addressed\", \"Functional consequences of dimerization not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded LRRK1's substrate and interaction repertoire to osteoclast actin (L-plastin Ser5) and to lysosomal exocytosis control via VAMP7 binding.\",\n      \"evidence\": \"Phosphoproteomics of WT vs Lrrk1-KO osteoclasts with KO mouse micro-CT; LRRK1-VAMP7 Co-IP with secretion and rigidity assays\",\n      \"pmids\": [\"30136304\", \"30240735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"VAMP7 regulation shown by a single lab without reciprocal validation\", \"Direct kinase dependence of VAMP7 effect not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified Rab7A Ser72 as a central LRRK1 substrate that recruits RILP and dynein-dynactin to drive perinuclear endosome transport, mechanistically unifying earlier trafficking observations.\",\n      \"evidence\": \"In vitro kinase assay, phospho-Rab7 S72 antibody, RILP Co-IP, and endosome motility imaging with dominant-negative/RNAi\",\n      \"pmids\": [\"31085713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling RILP-promoting vs RILP-neutral effects of pRab7A across studies\", \"In vivo relevance of Rab7 phosphorylation not yet defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated in patient-derived cells that LRRK1 kinase activity is required for L-plastin Ser5 phosphorylation and normal osteoclast resorption, directly tying the kinase to human bone disease.\",\n      \"evidence\": \"Patient osteoclasts with a kinase-disrupting splice mutation, phospho-L-plastin western blot, and bone resorption pit assays\",\n      \"pmids\": [\"32119750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other substrates contribute to the osteoclast defect not resolved\", \"Mechanism linking L-plastin pSer5 to resorption pit formation incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined LRRK1 substrate specificity and upstream regulation, showing it phosphorylates Rab7A (not Rab8A/Rab10), is activated by phorbol esters, is dephosphorylated by PPM1H, and is regulated independently of LRRK2's Rab29/VPS35 inputs.\",\n      \"evidence\": \"MS of LRRK1-KO vs WT cells, in vitro kinase profiling across Rab substrates, phorbol-ester stimulation, and inhibitor profiling\",\n      \"pmids\": [\"33459343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discrepancy with prior report on pRab7A-RILP coupling\", \"Identity of the PKC-coupled upstream signal not pinned down here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Integrated LRRK1 into multiple Rab7-dependent and cytoskeletal pathways: ULK1/2-ATG13-recruited mitophagy, PLK1-driven NDEL1 Ser155 phosphorylation for cilia disassembly, and PKC-mediated CORB-domain activation.\",\n      \"evidence\": \"Genetic epistasis and ectopic mitochondrial targeting for mitophagy; in vitro NDEL1 phosphorylation with dynein-2 Co-IP and cilia resorption; PKC isoform reconstitution with activation-site mutagenesis\",\n      \"pmids\": [\"36408770\", \"36254578\", \"36040231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct activation cues (PKC, PLK1, ULK) select specific substrate outputs unclear\", \"Spatial control restricting each substrate engagement not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved LRRK1's unique regulatory logic—dimer-dependent autoinhibition distinct from LRRK2—and placed EGFR/LRRK1 reactivation at ER-endosome contact sites via PTP1B.\",\n      \"evidence\": \"Cryo-EM of monomeric and dimeric LRRK1 with LRRK2 comparison; Co-IP, proximity ligation, and trafficking assays for the PTP1B-EGFR-LRRK1 axis\",\n      \"pmids\": [\"37857821\", \"36744428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation events relieve dimer autoinhibition structurally not shown\", \"Dynamics of LRRK1 monomer-dimer transition in cells unmeasured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Began broadening the substrate landscape by proposing Rab43 as a new LRRK1 target distinct from LRRK2's Rab set.\",\n      \"evidence\": \"In vitro kinase profiling against a Rab panel with MS phosphorylation profiling (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No cellular validation of Rab43 phosphorylation by LRRK1\", \"Preprint, not yet peer-reviewed\", \"Physiological role of any Rab43 phosphorylation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LRRK1's multiple upstream activation inputs (GTP, PKC, PLK1) are spatially and temporally coordinated to select among its diverse substrates across trafficking, mitosis, ciliogenesis, mitophagy, and bone remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking activation cue to substrate choice\", \"Limited in vivo substrate-phosphorylation data outside osteoclasts\", \"Structural mechanism coupling Roc/CORB phosphorylation to kinase activation not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 5, 8, 9, 14, 17]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 9, 15]},\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2, 4, 9]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2, 9, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 12, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB7A\", \"EGFR\", \"CDK5RAP2\", \"CLIP-170\", \"NDEL1\", \"VAMP7\", \"CARMA1\", \"ATG13\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}