{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Docking protein 3 (DOK3) is a versatile immunoregulatory adaptor that fine‐tunes receptor‐mediated signaling in a variety of immune cells. In B lymphocytes, DOK3 attenuates B‐cell receptor (BCR) signaling by sequestering the adaptor Grb2—thereby impairing the assembly of the Grb2–Sos complex—and by limiting calcium fluxes. This negative feedback regulation helps to balance BCR‐induced activation and is critical for proper plasma cell differentiation via modulation of inhibitory ligand expression (e.g., PD‐L1/PD‐L2)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In macrophages, DOK3 plays a context‐dependent role. It associates with immunoreceptor tyrosine‐based activation motif (ITAM)–bearing adaptors such as DAP12; upon phosphorylation by Src family kinases, DOK3 translocates to the plasma membrane and limits LPS‐induced extracellular signal–regulated kinase (ERK) activation and proinflammatory cytokine production, thereby restraining excessive inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n Conversely, DOK3 can also promote antiviral signaling by binding to TRAF3 and TBK1 to facilitate IRF3 activation and interferon‐β production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n Moreover, its protein levels are dynamically controlled through ubiquitin-mediated degradation via TRAF6, which modulates its inhibitory capacity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In neutrophils, DOK3 attenuates antifungal immunity by recruiting protein phosphatase 1 to dephosphorylate CARD9, thereby dampening NF-κB and JNK activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n In parallel, DOK3 is required for certain anti-inflammatory effects—such as those mediated by vitamin B6 through AMP-activated protein kinase (AMPK)—underscoring its broader role in maintaining immune homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its roles in myeloid cells, DOK3 contributes to B-cell fate by modulating early BCR signaling events; by attenuating calcium-dependent activation pathways, it promotes the expression of regulatory ligands that are essential for plasma cell differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n Consistent with these inhibitory functions, DOK3 sequesters Grb2—preventing its association with Shc—and thereby limits Ras–Erk pathway activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond classical immune cells, emerging evidence indicates that DOK3 also influences inflammatory processes in other contexts. In colonic neutrophils, DOK3 suppresses JAK2/STAT3 signaling to limit the production of inflammatory mediators and to maintain intestinal homeostasis, thus protecting against inflammatory bowel disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In the central nervous system, DOK3’s interaction with G-protein–coupled receptor 84 (GPR84) in microglia promotes inflammatory responses that contribute to neuropathic pain."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Moreover, in gliomas, elevated DOK3 expression correlates with greater infiltration of immunosuppressive, M2-polarized macrophages and with more aggressive disease progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings reveal that DOK3 functions as a context-dependent signaling modulator—capable of both restraining and facilitating downstream responses—to maintain the balance between activation and inhibition in immune and inflammatory pathways. Its multifaceted roles have important implications for host defense, autoimmunity, inflammation, and cancer.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tim Schnyder, Angelo Castello, Christoph Feest, et al. 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