{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSTAP‐2 is a multifunctional adaptor protein that acts as a central regulator of diverse signaling pathways in both innate and adaptive immunity. It interacts with members of the STAT family—dampening STAT5‐mediated cytokine responses while enhancing STAT3 activation—and associates with key proximal components of antigen receptor signaling, including the T cell receptor and CD3ζ motifs, thereby modulating IL-2 production and memory CD8⁺ T cell differentiation. In addition, STAP‐2 facilitates Fas-mediated apoptosis in T cells, in part through its direct interaction with caspase-8, and regulates integrin-mediated adhesion via promoting FAK degradation."}, {"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 innate immunity, STAP‐2 controls receptor‐mediated signal transduction in macrophages and mast cells. It binds directly to the c-Fms/M-CSF receptor through its PH domain, thereby attenuating M-CSF–induced tyrosine phosphorylation and downstream Akt/ERK signaling; indeed, loss of STAP‐2 enhances these pathways. In mast cells and basophils, STAP‐2 modulates FcεRI- and IL-33–induced signaling cascades that impact degranulation and cytokine production, and it also regulates intestinal inflammation by affecting chemokine and cytokine output from epithelial cells. Moreover, STAP‐2 plays an oncogenic role by binding to BCR-ABL where it upregulates its phosphorylation and alters chemokine receptor expression, a function further extended in melanoma cells where STAP‐2 stabilizes tyrosinase to influence tumor invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSTAP‐2 also orchestrates adaptive immune responses and lymphocyte development. In T cells, beyond enhancing TCR-proximal signaling via interactions with CD3ζ and LCK, STAP‐2 regulates downstream events that affect cell adhesion and effector differentiation; overexpression predisposes to exaggerated autoimmune inflammatory responses, whereas its deficiency has been linked to impaired activation-induced cell death and altered responses post-transplantation. In B cells, STAP‐2 modulates BCR-mediated signaling by binding LYN and CSK, thereby influencing antibody production and recovery following cytotoxic insults. Finally, emerging roles in metabolism have been uncovered as STAP‐2 forms a complex with CAP and c-Cbl to enhance GLUT4 translocation and promote adipocyte differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yuichi Sekine, Tetsuya Yamamoto, Taro Yumioka, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "STAP-2 Is a Novel Positive Regulator of TCR-Proximal Signals."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.2101014"}], "href": "https://doi.org/10.4049/jimmunol.2101014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35725273"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35725273"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Osamu Ikeda, Yuichi Sekine, Michinori Kakisaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STAP-2 regulates c-Fms/M-CSF receptor signaling in murine macrophage Raw 264.7 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2007.05.030"}], "href": "https://doi.org/10.1016/j.bbrc.2007.05.030"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17512498"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17512498"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Osamu Ikeda, Yuichi Sekine, Ryuta Muromoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Enhanced c-Fms/M-CSF receptor signaling and wound-healing process in bone marrow-derived macrophages of signal-transducing adaptor protein-2 (STAP-2) deficient mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Pharm Bull (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1248/bpb.31.1790"}], "href": "https://doi.org/10.1248/bpb.31.1790"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18758078"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18758078"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yuichi Sekine, Keigo Nishida, Satoru Yamasaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Signal-transducing adaptor protein-2 controls the IgE-mediated, mast cell-mediated anaphylactic responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1300886"}], "href": "https://doi.org/10.4049/jimmunol.1300886"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24616480"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24616480"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Natsuko Fujita, Kenji Oritani, Michiko Ichii, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Signal-transducing adaptor protein-2 promotes generation of functional long-term memory CD8+ T cells by preventing terminal effector differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.15403"}], "href": "https://doi.org/10.18632/oncotarget.15403"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28430604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28430604"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Michiko Ichii, Kenji Oritani, Jun Toda, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Graft-versus-host disease develops in mice transplanted with lymphocyte-depleted bone marrow cells from signal-transducing adaptor protein-2 transgenic mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2020.12.080"}], "href": "https://doi.org/10.1016/j.bbrc.2020.12.080"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33388414"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33388414"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Jun-Ichi Kashiwakura, Shoya Kawahara, Iori Inagaki, et al. 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