{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRALGDS functions predominantly as a guanine nucleotide exchange factor that activates the small GTPase Ral in response to diverse extracellular signals. In neutrophils, for example, RALGDS is sequestered in the cytosol within a beta‐arrestin complex, from which it is released upon chemoattractant (fMLP) stimulation to trigger Ras‐independent Ral activation and consequent cytoskeletal rearrangements indispensable for granule release."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, as a direct effector of Ras, RALGDS mediates signal transduction pathways implicated in oncogenesis, including regulation of choline kinase activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in cytoskeletal dynamics and metabolic regulation, RALGDS critically impacts cancer progression and cell cycle control. Activation of the RalGEF pathway, in which RALGDS participates, has been linked to organ‐specific metastasis; in prostate cancer models, this pathway preferentially promotes bone metastases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, studies show that activation of the Ras–RalGEF–Ral axis, mediated by RALGDS, can override DNA damage-induced G2 arrest by disrupting CDC2 inhibitory phosphorylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Intricate molecular interactions have also been detailed, with vibrational spectroscopy and simulation studies revealing that charge differences—exemplified by Rap1A mutations—facilitate RALGDS’s selective binding to Ras versus Rap, thereby tuning its downstream signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRALGDS also plays pivotal roles in nutrient sensing and exocytosis. It is indispensable for the activation of mTOR complex 1 in response to extracellular amino acid and glucose availability through RalA activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In endothelial cells, RALGDS is required for the regulated exocytosis of Weibel–Palade bodies, a function that depends on its interaction with calmodulin and is disrupted by dominant-negative mutants."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Furthermore, tumor suppressor merlin binds to RALGDS and inhibits its capacity to activate RalA, thereby restraining oncogenic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Moshmi Bhattacharya, Pieter H Anborgh, Andy V Babwah, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb821"}], "href": "https://doi.org/10.1038/ncb821"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12105416"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12105416"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ana Ramírez de Molina, Verónica Penalva, Luisa Lucas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of choline kinase activity by Ras proteins involves Ral-GDS and PI3K."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1205144"}], "href": "https://doi.org/10.1038/sj.onc.1205144"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11840339"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11840339"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "JuanJuan Yin, Claire Pollock, Kirsten Tracy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00955-07"}], "href": "https://doi.org/10.1128/MCB.00955-07"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17709381"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17709381"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Larissa S Agapova, Julia L Volodina, Peter M Chumakov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of Ras-Ral pathway attenuates p53-independent DNA damage G2 checkpoint."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M405007200"}], "href": "https://doi.org/10.1074/jbc.M405007200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15208305"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15208305"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Christina M Ragain, Robert W Newberry, Andrew W Ritchie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of electrostatics in differential binding of RalGDS to Rap mutations E30D and K31E investigated by vibrational spectroscopy of thiocyanate probes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Phys Chem B (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/jp303272y"}], "href": "https://doi.org/10.1021/jp303272y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22738401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22738401"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Gloria Fuentes, Alfonso Valencia "}, {"type": "b", "children": [{"type": "t", "text": "Ras classical effectors: new tales from in silico complexes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Trends Biochem Sci (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.tibs.2009.07.001"}], "href": "https://doi.org/10.1016/j.tibs.2009.07.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19801192"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19801192"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Tomohiko Maehama, Masahiko Tanaka, Hiroshi Nishina, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RalA functions as an indispensable signal mediator for the nutrient-sensing system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M805822200"}], "href": "https://doi.org/10.1074/jbc.M805822200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18948269"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18948269"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Mariska G Rondaij, Ruben Bierings, Ellen L van Agtmaal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Guanine exchange factor RalGDS mediates exocytosis of Weibel-Palade bodies from endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2007-07-099309"}], "href": "https://doi.org/10.1182/blood-2007-07-099309"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18417737"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18417737"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Chung Hun Ryu, Sae-Woong Kim, Kyu Hwa Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The merlin tumor suppressor interacts with Ral guanine nucleotide dissociation stimulator and inhibits its activity."}]}, {"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.1208633"}], "href": "https://doi.org/10.1038/sj.onc.1208633"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16007223"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16007223"}]}]}]}