{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Leucine‐rich repeat kinase 1 (LRRK1) is a multifunctional signaling protein that integrates GTPase and kinase activities to modulate a diverse range of cellular processes. Functional studies have shown that LRRK1 acts as a GTP‐regulated kinase whose GTP binding enhances its kinase activity, and that full‐length LRRK1 readily forms homodimeric complexes, highlighting its importance as a molecular scaffold."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, LRRK1 is implicated in the regulation of cell division; it is phosphorylated by Polo‐like kinase 1 (PLK1) at centrosomes, where it activates CDK5RAP2 to nucleate astral microtubules and thereby ensure proper mitotic spindle orientation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n LRRK1 also plays a critical role in the immune system by modulating B‐cell receptor signaling. In LRRK1‐deficient B cells, impaired NF‐κB activation and defective proliferation and survival have been observed, leading to abnormal B‐cell maturation and altered immunoglobulin production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, LRRK1 contributes to the maintenance of cellular homeostasis through the regulation of autophagic flux. Upon induction of autophagy, LRRK1 is recruited to autolysosomes—via an association with VAMP7—where it activates the Rab7 GTPase‐activating protein TBC1D2 to terminate Rab7 signaling and facilitate proper autolysosome formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the skeleton, LRRK1 is essential for osteoclast function and bone remodeling. Loss‐of‐function mutations in LRRK1 lead to severe osteosclerotic metaphyseal dysplasia and osteopetrosis by perturbing the activation of small GTPases like RAC1/Cdc42 and impairing cytoskeletal organization required for bone resorption."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n LRRK1 further regulates endosomal trafficking of the epidermal growth factor receptor (EGFR). Its kinase activity mediates phosphorylation events—such as that of Rab7—that promote the recruitment of dynein–dynactin complexes for the proper movement of EGFR‐containing endosomes toward the perinuclear region."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In addition, EGFR itself can feedback to modulate LRRK1 activity via tyrosine phosphorylation, and interactions with proteins such as FIH‐1 further influence EGFR turnover."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Emerging evidence also implicates LRRK1 in oncogenic processes and growth regulation. For instance, in T‐cell acute lymphoblastic leukemia, LRRK1 is targeted by a long noncoding RNA/miR‐195–5p axis that modulates cell proliferation and survival"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and copy number variations encompassing LRRK1 have been associated with overgrowth phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Although candidate gene studies have explored LRRK1 variants in Parkinson’s disease and essential tremor, current findings suggest these variants are infrequent and unlikely to be major contributors to neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore the broad and context‐dependent roles of LRRK1 in regulating cell division, immune responses, autophagy, endosomal trafficking, and bone metabolism. The integration of its GTPase and kinase activities enables LRRK1 to function as an important regulatory node in diverse signaling pathways.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daniel Korr, Luisella Toschi, Peter Donner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2005.08.015"}], "href": "https://doi.org/10.1016/j.cellsig.2005.08.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16243488"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16243488"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Laura Civiero, Renée Vancraenenbroeck, Elisa Belluzzi, et al. 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