{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMEKK3, a member of the MAPK kinase kinase family, has emerged as a central mediator of inflammatory signaling cascades. It transduces signals initiated by receptors such as the interleukin‐1 receptor (IL‐1R), Toll‐like receptors (TLRs), and lysophosphatidic acid (LPA) receptors to promote the activation of NF‑κB and downstream MAP kinases (including JNK, p38, and selective activation of ERK pathways). In these settings, MEKK3 assembles into distinct protein complexes—often partnering with adaptors such as TRAF6 or 14‑3‑3—to control the kinetics and amplitude of cytokine‐ and pathogen‐induced responses as well as noncanonical NF‑κB signaling. These activities have been implicated in both innate immune functions and neuroinflammatory processes, underscoring the versatility of MEKK3 in orchestrating responses to pro‐inflammatory stimuli."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the endothelial and cardiovascular systems, MEKK3 plays a critical role in vascular development and integrity. By interacting with proteins such as CCM2 and through regulation of transcription factors (e.g., KLF2/4) and proteases involved in extracellular matrix remodeling, MEKK3 influences endocardial cushion formation, heart development, and the maintenance of neurovascular integrity. Dysregulation of MEKK3 signaling—whether by aberrant activation or via genetically acquired mutations—has been causally linked to conditions such as cerebral cavernous malformations and defects in vessel formation during embryogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these roles, MEKK3 is a pivotal regulator in immune cell function and other cellular contexts. In adaptive immunity, for example, it modulates T cell receptor–mediated signaling, thereby influencing T cell activation, differentiation, and homeostasis—processes that are critical for effective cytokine production and cellular proliferation. Its scaffolding functions, facilitated by domains such as the PB1 region, allow MEKK3 to couple with specific kinases (e.g., MEK5 for ERK5 activation) and regulators (such as NBR1 in adipose tissue inflammation), thereby fine‐tuning the responses in platelets, brown adipocytes, and even tumor‐initiating cells. Together, these findings highlight that MEKK3 is a versatile integrator of extracellular cues, orchestrating diverse responses from inflammatory gene induction to vascular remodeling and T cell immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Qiaojia Huang, Jianhua Yang, Yong Lin, et al. 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