{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRho GTPase signaling is central to the regulation of diverse cellular functions including cytoskeletal dynamics, cell adhesion, migration, and vascular development. Several studies have characterized key regulators—such as ARAP3, a GTPase‐activating protein that modulates RhoA, Rac1, and Arf6 activity—and adaptor molecules that mediate responses downstream of growth factor and integrin receptors. For example, ARAP3 is phosphorylated by Src-family kinases and PI3-kinase activation, leading to altered cell spreading and morphological changes during adhesion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " ARAP3 also controls neutrophil adhesion‐dependent functions by ensuring neutrophils remain quiescent until proper activation is achieved"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", while it is essential for proper sprouting angiogenesis as demonstrated in murine models"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In addition, studies using gene knockout approaches have revealed roles for other actin-regulatory proteins—such as the Nck adaptor proteins—in coordinating Rho GTPase–dependent cytoskeletal rearrangements"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", whereas investigation into ARAP3 function in hematopoietic and endothelial cells confirmed its crucial role during embryonic vascular formation yet minimal effects on adult hematopoiesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Finally, ARAP3 has been implicated in protecting against excessive inflammation-induced microvascular permeability in the lung, highlighting the importance of precise Rho signaling regulation in maintaining vascular barrier integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn contrast to these protein regulators, the long non-coding RNA VAV3-AS1—a transcript antisense to the VAV3 gene, which encodes a Rho guanine nucleotide exchange factor—has emerged as a potential modulator of Rho/Rac signaling that impacts vascular function. A recent genetic association study found that the G allele of the VAV3-AS1 rs11185222 polymorphism is linked to an increased risk of hypertension, suggesting that alterations in VAV3-AS1 expression may influence blood pressure regulation by modifying Rho/Rac pathway activity and consequently vascular smooth muscle contractility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stacey T T I, Zhongzhen Nie, Ashley Stewart, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ARAP3 is transiently tyrosine phosphorylated in cells attaching to fibronectin and inhibits cell spreading in a RhoGAP-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.01526"}], "href": "https://doi.org/10.1242/jcs.01526"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15546919"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15546919"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Laure Gambardella, Karen E Anderson, Claudia Nussbaum, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The GTPase-activating protein ARAP3 regulates chemotaxis and adhesion-dependent processes in neutrophils."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2010-10-312959"}], "href": "https://doi.org/10.1182/blood-2010-10-312959"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21490342"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21490342"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Laure Gambardella, Myriam Hemberger, Bethany Hughes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PI3K signaling through the dual GTPase-activating protein ARAP3 is essential for developmental angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.2001026"}], "href": "https://doi.org/10.1126/scisignal.2001026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20978237"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20978237"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Joëlle Kartopawiro, Neil I Bower, Tara Karnezis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Arap3 is dysregulated in a mouse model of hypotrichosis-lymphedema-telangiectasia and regulates lymphatic vascular development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddt518"}], "href": "https://doi.org/10.1093/hmg/ddt518"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24163130"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24163130"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Aino Ruusala, Tony Pawson, Carl-Henrik Heldin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nck adapters are involved in the formation of dorsal ruffles, cell migration, and Rho signaling downstream of the platelet-derived growth factor beta receptor."}]}, {"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.M800913200"}], "href": "https://doi.org/10.1074/jbc.M800913200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18765673"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18765673"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yiwen Song, Jing Jiang, Sonja Vermeren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ARAP3 functions in hematopoietic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0116107"}], "href": "https://doi.org/10.1371/journal.pone.0116107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25542002"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25542002"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Julia Y Chu, Barry McCormick, Kruthika Sundaram, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ARAP3 protects from excessive formylated peptide-induced microvascular leakage by acting on endothelial cells and neutrophils."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pathol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/path.6288"}], "href": "https://doi.org/10.1002/path.6288"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38734878"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38734878"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "José Pablo Miramontes-González, Ricardo Usategui-Martín, Javier Martín-Vallejo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VAV3 rs7528153 and VAV3-AS1 rs1185222 polymorphisms are associated with an increased risk of developing hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Intern Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejim.2020.05.014"}], "href": "https://doi.org/10.1016/j.ejim.2020.05.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32540412"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32540412"}]}]}]}