{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRASGRP1 is a pivotal Ras‐guanine nucleotide exchange factor that transduces receptor‐initiated signals by catalyzing the exchange of GDP for GTP on Ras, thereby triggering the downstream MAPK cascade. Studies have demonstrated that upon activation by upstream signals—such as Src‐dependent phospholipase Cγ1–mediated diacylglycerol production—RASGRP1 translocates to specific intracellular compartments including the Golgi apparatus, where it instigates spatially distinct Ras signaling. Moreover, biophysical and crystallographic analyses have revealed that RASGRP1 is maintained in an autoinhibited conformation that is released by conformational rearrangements, with key residues acting as pH‐sensitive switches to fine‐tune its activation status."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn lymphocytes, RASGRP1 plays essential roles in both the initiation and modulation of receptor‐mediated Ras signaling. Its activity is crucial for T‐cell receptor–induced ERK activation that governs thymocyte positive selection and the maintenance of tonic signals required for sustaining T‐cell receptor expression on resting cells. Aberrant expression, alternative splicing, or mutations in RASGRP1 have been linked to immune dysregulation manifested as immunodeficiency, systemic autoimmunity, and T‐cell leukemogenesis—in some cases cooperating with oncogenic signals (for example, through NOTCH1 mutations) to drive malignant transformation. These findings underscore that both excessive and diminished RASGRP1 activity impair normal immune homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in lymphocyte signaling, genetic and functional studies have implicated RASGRP1 in a broad spectrum of pathologies. Genome‐wide association analyses have linked RASGRP1 variants to type 2 diabetes risk and altered glycemic indices, while other studies point to its involvement in neuropsychiatric conditions such as schizophrenia via modulation of dopamine signaling. In addition, RASGRP1 influences oncogenic processes in non‐lymphoid tissues—it may act as a tumor suppressor in colorectal cancer and modulate hepatocellular carcinoma cell proliferation—and contributes to angiogenic responses in endothelial cells. Detailed regulatory mapping of RASGRP1 loci has further identified enhancer regions and transcription factors that govern its dosage, thereby connecting its precise expression levels to autoimmunity and lymphoproliferative disease. Collectively, these studies illustrate that RASGRP1 functions as a multifaceted signal regulator whose finely tuned activity is critical for normal cellular homeostasis in diverse tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Trever G Bivona, Ignacio Pérez De Castro, Ian M Ahearn, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "A Histidine pH sensor regulates activation of the Ras-specific guanine nucleotide exchange factor RasGRP1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.29002"}], "href": "https://doi.org/10.7554/eLife.29002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28952923"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28952923"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Mark B Klinger, Benoit Guilbault, Rebecca E Goulding, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deregulated expression of RasGRP1 initiates thymic lymphomagenesis independently of T-cell receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1208334"}], "href": "https://doi.org/10.1038/sj.onc.1208334"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15829980"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15829980"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Shinsuke Yasuda, Richard L Stevens, Tomoko Terada, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defective expression of Ras guanyl nucleotide-releasing protein 1 in a subset of patients with systemic lupus erythematosus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.179.7.4890"}], "href": "https://doi.org/10.4049/jimmunol.179.7.4890"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17878389"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17878389"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "T Oki, J Kitaura, N Watanabe-Okochi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/leu.2011.328"}], "href": "https://doi.org/10.1038/leu.2011.328"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22116551"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22116551"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "O Ksionda, A A Melton, J Bache, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RasGRP1 overexpression in T-ALL increases basal nucleotide exchange on Ras rendering the Ras/PI3K/Akt pathway responsive to protumorigenic cytokines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2015.431"}], "href": "https://doi.org/10.1038/onc.2015.431"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26549032"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26549032"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Elisabeth Salzer, Deniz Cagdas, Miroslav Hons, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.3575"}], "href": "https://doi.org/10.1038/ni.3575"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27776107"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27776107"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Agnes Czikora, Noemi Kedei, Heather Kalish, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Importance of the REM (Ras exchange) domain for membrane interactions by RasGRP3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Biomembr (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamem.2017.09.010"}], "href": "https://doi.org/10.1016/j.bbamem.2017.09.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28912101"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28912101"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Ido Somekh, Benjamin Marquardt, Yanshan Liu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Nurr1 performs its anti-inflammatory function by regulating RasGRP1 expression in neuro-inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-020-67549-7"}], "href": "https://doi.org/10.1038/s41598-020-67549-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32612143"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32612143"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Masanori Horinouchi, Mariko Yagi, Hiroyuki Imanishi, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Sp1-regulated transcription of RasGRP1 promotes hepatocellular carcinoma (HCC) proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Liver Int (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/liv.13757"}], "href": "https://doi.org/10.1111/liv.13757"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29655291"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29655291"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Julio E Molineros, Bhupinder Singh, Chikashi Terao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanistic Characterization of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "RASGRP1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Variants Identifies an hnRNP-K-Regulated Transcriptional Enhancer Contributing to SLE Susceptibility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Immunol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fimmu.2019.01066"}], "href": "https://doi.org/10.3389/fimmu.2019.01066"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31164884"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31164884"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Oghenekevwe M Gbenedio, Caroline Bonnans, Delphine Grun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RasGRP1 is a potential biomarker to stratify anti-EGFR therapy response in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JCI Insight (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/jci.insight.127552"}], "href": "https://doi.org/10.1172/jci.insight.127552"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31237864"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31237864"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Hidenori Ito, Rika Morishita, Mariko Noda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biochemical and morphological characterization of SEPT1 in mouse brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Mol Morphol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00795-020-00248-4"}], "href": "https://doi.org/10.1007/s00795-020-00248-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32146512"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32146512"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Zineb Rchiad, Malak Haidar, Hifzur Rahman Ansari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel tumour suppressor roles for GZMA and RASGRP1 in Theileria annulata-transformed macrophages and human B lymphoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Microbiol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cmi.13255"}], "href": "https://doi.org/10.1111/cmi.13255"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32830401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32830401"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Matthijs J D Baars, Thera Douma, Dimitre R Simeonov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Immunol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/eji.201948451"}], "href": "https://doi.org/10.1002/eji.201948451"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33065764"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33065764"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Arianna De Rosa, Anna Di Maio, Silvia Torretta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Abnormal RasGRP1 Expression in the Post-Mortem Brain and Blood Serum of Schizophrenia Patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomolecules (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/biom12020328"}], "href": "https://doi.org/10.3390/biom12020328"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35204828"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35204828"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Tu Chun Hsu, Gisele O L Rodrigues, Hila Winer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Focused Review of Ras Guanine Nucleotide-Releasing Protein 1 in Immune Cells and Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms24021652"}], "href": "https://doi.org/10.3390/ijms24021652"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36675167"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36675167"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Jiecan Zhou, Bo Xu, Fazhong He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of RASGRP1 polymorphism with vascular complications in Chinese diabetic patients with glycemic control and antihypertensive treatment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Diabetol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12933-024-02267-2"}], "href": "https://doi.org/10.1186/s12933-024-02267-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38730425"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38730425"}]}]}]}