{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRIN3 is a multifunctional protein that plays a pivotal role in regulating early endocytic trafficking. It acts as a guanine nucleotide exchange factor (GEF) for Rab proteins—most notably for Rab5 and Rab31—thereby stimulating and stabilizing the GTP-bound forms needed for membrane budding and vesicular transport. In addition, RIN3 is targeted to specific cytoplasmic vesicles where it interacts via its proline‐rich domains with partners such as amphiphysin II and CD2AP, coordinating the transport of cargo (e.g., transferrin and mannose 6-phosphate receptor) and modulating the early steps of receptor-mediated endocytosis. Its activity is further regulated by tyrosine phosphorylation signals, which are proposed to relieve an autoinhibitory interaction involving its Ras association domain."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have implicated RIN3 in skeletal physiology and pathologies. Variants in RIN3 are associated with differences in bone mineral density at various skeletal sites, and both common and rare coding changes in RIN3 contribute to susceptibility to Paget’s disease of bone by potentially modulating osteoclast function and even influencing the age of disease onset."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of neurodegeneration, RIN3 has emerged as an important player in Alzheimer’s disease. Genetic investigations suggest that RIN3 may be a novel risk factor for early‐onset Alzheimer’s disease, and mechanistic studies have demonstrated that RIN3 interacts with neuronal isoforms of BIN1 to sequester it into Rab5‐positive endosomes. This interaction delays the endocytosis of amyloid precursor protein, thereby reducing its cleavage by β‐secretase and ultimately lowering amyloid‑β generation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroaki Kajiho, Kota Saito, Kyoko Tsujita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.00718"}], "href": "https://doi.org/10.1242/jcs.00718"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12972505"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12972505"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Manabu Yoshikawa, Hiroaki Kajiho, Kyoko Sakurai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tyr-phosphorylation signals translocate RIN3, the small GTPase Rab5-GEF, to early endocytic vesicles."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2008.05.027"}], "href": "https://doi.org/10.1016/j.bbrc.2008.05.027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18486601"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18486601"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Hiroaki Kajiho, Kyoko Sakurai, Tomohiro Minoda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of RIN3 as a guanine nucleotide exchange factor for the Rab5 subfamily GTPase Rab31."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.172445"}], "href": "https://doi.org/10.1074/jbc.M110.172445"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21586568"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21586568"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Evgenia Rouka, Philip C Simister, Melanie Janning, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential Recognition Preferences of the Three Src Homology 3 (SH3) Domains from the Adaptor CD2-associated Protein (CD2AP) and Direct Association with Ras and Rab Interactor 3 (RIN3)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.637207"}], "href": "https://doi.org/10.1074/jbc.M115.637207"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26296892"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26296892"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Christine Janson, Noriyuki Kasahara, George C Prendergast, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIN3 is a negative regulator of mast cell responses to SCF."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0049615"}], "href": "https://doi.org/10.1371/journal.pone.0049615"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23185384"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23185384"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "John P Kemp, Carolina Medina-Gomez, Karol Estrada, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1004423"}], "href": "https://doi.org/10.1371/journal.pgen.1004423"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24945404"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24945404"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Mahéva Vallet, Dinesh C Soares, Sachin Wani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeted sequencing of the Paget's disease associated 14q32 locus identifies several missense coding variants in RIN3 that predispose to Paget's disease of bone."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddv068"}], "href": "https://doi.org/10.1093/hmg/ddv068"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25701875"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25701875"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Raphaël De Ridder, Eveline Boudin, Geert Vandeweyer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic Variation in RIN3 in the Belgian Population Supports Its Involvement in the Pathogenesis of Paget's Disease of Bone and Modifies the Age of Onset."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Calcif Tissue Int (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00223-019-00530-3"}], "href": "https://doi.org/10.1007/s00223-019-00530-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30726512"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30726512"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Brian W Kunkle, Badri N Vardarajan, Adam C Naj, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JAMA Neurol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1001/jamaneurol.2017.1518"}], "href": "https://doi.org/10.1001/jamaneurol.2017.1518"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28738127"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28738127"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Raja Bhattacharyya, Catarina Amelia Fidalgo Teves, Alexandra Long, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The neuronal-specific isoform of BIN1 regulates β-secretase cleavage of APP and Aβ generation in a RIN3-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-022-07372-4"}], "href": "https://doi.org/10.1038/s41598-022-07372-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35241726"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35241726"}]}]}]}