{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRic8A functions as a non‐receptor guanine nucleotide exchange factor that is essential for proper cell division. In mammalian cells, Ric8A localizes to key mitotic structures—including the cell cortex, spindle poles, centromeres, central spindle, and midbody—and organizes a cortical signaling complex required for accurate metaphase spindle orientation. In addition, Ric8A levels and conformational states are tightly regulated during mitosis, and diminished Ric8A expression or interference with its engagement with Gα(i) prolongs mitosis and disrupts cytokinesis, leading to delays in abscission and multinucleation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in cell division, Ric8A couples receptor tyrosine kinase signals to heterotrimeric G proteins to regulate actin cytoskeletal dynamics. For example, growth factor–stimulated pathways require Ric8A to effectively transmit signals to Gα(13) for dynamic dorsal ruffle turnover, a process that is critical for efficient cell migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRic8A is also intricately involved in modulating GPCR-associated signaling complexes. Studies have revealed that Ric8A participates in non-conventional G protein signaling by facilitating the dissociation of complexes involving regulators such as RGS14 from Gα(i) subunits upon receptor agonist activation. In neuronal cells, for instance, the adhesion molecule NCAM180 recruits Ric8A to the plasma membrane in a dose-dependent fashion to potentiate β-adrenergic receptor responses, whereas interactions with AGS3-containing complexes appear not to result in guanine nucleotide exchange under cellular conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these signaling roles, Ric8A serves as a molecular chaperone for G protein α subunits. It prevents the polyubiquitination and subsequent proteasomal degradation of select Gα proteins, such as Gα(i2) and Gα(q), thereby stabilizing their cellular levels. Structural investigations have demonstrated that Ric8A cradles the Ras-like domain of nascent Gα subunits—positioning critical helices to ensure proper folding prior to GTP-mediated release. This chaperone activity is modulated by dual phosphorylation events, mediated by CK2, which are indispensable for high-affinity interactions with Gα proteins and optimal GEF function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, within neuronal systems, Ric8A is a key modulator of synaptic properties. In Drosophila, Ric8A interacts selectively with the calcium sensor Frequenin (NCS-1 homolog) to control synapse number and neurotransmitter release by regulating Gα(s) signaling, delineating a pathway that differentially controls synaptic structure and function. Moreover, studies in models of pediatric encephalopathies indicate that pathogenic mutations in Gα(o) provoke aberrantly high interactions with Ric8A (and its paralog Ric8B), resulting in neomorphic signaling activities that contribute to disease severity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Geoffrey E Woodard, Ning-Na Huang, Hyeseon Cho, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ric-8A and Gi alpha recruit LGN, NuMA, and dynein to the cell cortex to help orient the mitotic spindle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00394-10"}], "href": "https://doi.org/10.1128/MCB.00394-10"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20479129"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20479129"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Cedric Boularan, Olena Kamenyeva, Hyeseon Cho, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Resistance to inhibitors of cholinesterase (Ric)-8A and Gαi contribute to cytokinesis abscission by controlling vacuolar protein-sorting (Vps)34 activity."}]}, {"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.0086680"}], "href": "https://doi.org/10.1371/journal.pone.0086680"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24466196"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24466196"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Limin Wang, Dagang Guo, Bowen Xing, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Resistance to inhibitors of cholinesterase-8A (Ric-8A) is critical for growth factor receptor-induced actin cytoskeletal reorganization."}]}, {"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.M111.253427"}], "href": "https://doi.org/10.1074/jbc.M111.253427"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21771786"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21771786"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Christopher P Vellano, Ellen M Maher, John R Hepler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "G protein-coupled receptors and resistance to inhibitors of cholinesterase-8A (Ric-8A) both regulate the regulator of g protein signaling 14 RGS14·Gαi1 complex in live cells."}]}, {"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.M111.274928"}], "href": "https://doi.org/10.1074/jbc.M111.274928"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21880739"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21880739"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Marie-Claude Amoureux, Stéphane Nicolas, Geneviève Rougon "}, {"type": "b", "children": [{"type": "t", "text": "NCAM180 regulates Ric8A membrane localization and potentiates β-adrenergic response."}]}, {"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.0032216"}], "href": "https://doi.org/10.1371/journal.pone.0032216"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22384181"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22384181"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Man K Tse, Christina J Morris, Mingjie Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activator of G protein signaling 3 forms a complex with resistance to inhibitors of cholinesterase-8A without promoting nucleotide exchange on Gα(i3)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biochem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11010-014-2289-7"}], "href": "https://doi.org/10.1007/s11010-014-2289-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25480567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25480567"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kanako Chishiki, Sachiko Kamakura, Satoru Yuzawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitination of the heterotrimeric G protein α subunits Gαi2 and Gαq is prevented by the guanine nucleotide exchange factor Ric-8A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2013.04.103"}], "href": "https://doi.org/10.1016/j.bbrc.2013.04.103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23665327"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23665327"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Alpay Burak Seven, Daniel Hilger, Makaía M Papasergi-Scott, et al. 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