{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nC3orf22 – which appears to be functionally synonymous with the dual‐specificity phosphatase DUSP2 (also known as PAC1) – plays important roles in modulating immune cell activation and differentiation. It has been shown to negatively regulate the effector functions of T cells by dephosphorylating key signaling molecules such as STAT3, thereby restraining TH17 cell development and the release of proinflammatory cytokines. In the cancer setting, elevated levels of this phosphatase in tumor‐infiltrating lymphocytes are linked with T cell exhaustion, reduced proliferative capacity, and impaired antitumor immunity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, C3orf22/DUSP2 exhibits conditional catalytic activity; it is essentially inactive in isolation but becomes activated upon direct interaction with its substrates. For instance, its association with ERK2 triggers dephosphorylation activity critical for MAP kinase signal termination. Additionally, specific amino acid residues (such as Arg294 and Arg295) are crucial for its substrate binding and catalytic function. Transcriptional regulation studies further indicate that factors like BATF2 bind to the DUSP2 promoter and enhance its expression, thereby linking TLR and NF-κB signaling to phosphatase-mediated regulation of cytokine production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical immune regulatory functions, C3orf22/DUSP2 is implicated in a range of physiological and pathological processes. In the thymus, its expression—tightly connected to PACAP/PAC1 signaling—correlates inversely with thymus index and directly with apoptosis, suggesting roles in lymphoid organ homeostasis under stress conditions. In metabolic contexts, the absence of DUSP2 has been associated with only marginal protection against obesity-associated inflammation and insulin resistance, with subtle sex‐dependent differences. Moreover, emerging evidence points to a contribution of DUSP2 in hyperglycemia-induced vascular endothelial dysfunction and in modulating chondrogenesis during atherogenesis, linking it to vascular disease progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dan Lu, Liang Liu, Xin Ji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.3278"}], "href": "https://doi.org/10.1038/ni.3278"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26479789"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26479789"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": " Dan Lu, Liang Liu, Yizhe Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The phosphatase PAC1 acts as a T cell suppressor and attenuates host antitumor immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41590-019-0577-9"}], "href": "https://doi.org/10.1038/s41590-019-0577-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31932812"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31932812"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Qiang Zhang, Michaela Muller, Can Hao Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New insights into the catalytic activation of the MAPK phosphatase PAC-1 induced by its substrate MAPK ERK2 binding."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2005.10.006"}], "href": "https://doi.org/10.1016/j.jmb.2005.10.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16288922"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16288922"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hisashi Kanemaru, Fumihiro Yamane, Hiroki Tanaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BATF2 activates DUSP2 gene expression and up-regulates NF-κB activity via phospho-STAT3 dephosphorylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int Immunol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/intimm/dxy023"}], "href": "https://doi.org/10.1093/intimm/dxy023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29534174"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29534174"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Huahua Zhang, Rongjie Yu, Xiaofei Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The expression of PAC1 increases in the degenerative thymus and low dose PACAP protects female mice from cyclophosphamide induced thymus atrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Peptides (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.peptides.2012.09.009"}], "href": "https://doi.org/10.1016/j.peptides.2012.09.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23000307"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23000307"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Graeme I Lancaster, Michael J Kraakman, Helene L Kammoun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The dual-specificity phosphatase 2 (DUSP2) does not regulate obesity-associated inflammation or insulin resistance in mice."}]}, {"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.0111524"}], "href": "https://doi.org/10.1371/journal.pone.0111524"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25375135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25375135"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Xinmiao Jiang, Qiong Yan, Jiaqi He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interfering with Dusp2 alleviates high glucose-induced vascular endothelial cell dysfunction by promoting p38 MAPK pathway activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2023.113720"}], "href": "https://doi.org/10.1016/j.yexcr.2023.113720"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37479052"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37479052"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "C Blümm, G A Bonaterra, H Schwarzbach, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PAC1 deficiency reduces chondrogenesis in atherosclerotic lesions of hypercholesterolemic ApoE-deficient mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cardiovasc Disord (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12872-023-03600-5"}], "href": "https://doi.org/10.1186/s12872-023-03600-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37980508"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37980508"}]}]}]}