{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe PTGER3‐encoded prostaglandin E₂ receptor subtype EP3 is a highly versatile receptor that in many tissues mediates inhibitory as well as modulatory signals. In breast stromal cells, for example, activation of EP3 opposes the stimulatory effects of other EP receptors on aromatase expression, suggesting that EP3 signaling may temper estrogen biosynthesis and thus influence the development of hormone‐dependent breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In pancreatic islets, an upregulation of EP3 reduces intracellular cAMP levels and dampens glucose-stimulated insulin secretion, thereby contributing to β–cell dysfunction in type 2 diabetes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Similar inhibitory signaling via EP3 plays key roles in the hypothalamo–pituitary–adrenal axis activation in response to endotoxin, modulates chondrocyte responses to mechanical shear by curtailing inflammatory interleukin-6 synthesis, and even contributes to thrombin-induced brain injury through promotion of cytotoxic and proinflammatory cascades."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the vasculature and inflammatory pain pathways the EP3 receptor also exerts pivotal functions. In platelets, EP3 activation augments aggregation and thereby promotes atherothrombosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", while in hair follicles and vascular smooth muscle cells its expression is widespread, contributing to tissue-specific contractile and growth inhibitory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In sensory neurons, co-expression with TRPV1 enables EP3 to counterbalance the pronociceptive effects mediated by EP2/EP4 activation thereby producing analgesia under inflammatory conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Moreover, in T–leukemia cells EP3 cooperates with EP4 to regulate prolactin gene expression via modulation of intracellular calcium and cAMP"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", and differential post-endocytic trafficking of EP3 splice variants—demonstrated in heterologous systems—further highlights the receptor’s complex regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In addition, EP3 signaling contributes to dendritic cell development by regulating Flt3 receptor expression and downstream survival pathways"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", while in prostate and myometrial tissues, reduced EP3 expression correlates with increased androgen receptor levels and tumor progression or, alternatively, with enhanced contractile responses in labor."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Finally, studies in bladder afferent pathways, keratinocytes, and even in atherosclerotic lesions point to additional roles for EP3 in modulating neuronal excitability, cellular growth, and vascular reactivity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn several malignancies EP3 receptor signaling displays context-dependent effects. In ovarian cancer and cholangiocarcinoma, activation of specific EP3 splice variants triggers oncogenic signaling cascades (via Src, EGFR, PI3K/AKT and stabilization of β-catenin), thereby promoting tumor growth, invasion, and chemoresistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " In prostate cancer and cervical cancer, decreased EP3 expression is associated with disease progression, where restoration of EP3 signaling can suppress proliferation and modulate receptor expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "27"}]}, {"type": "t", "text": " Structural studies have now provided atomic details of ligand binding to EP3, while recent work in hetero–oligomerization has revealed that EP3 can interact with receptors such as that for ghrelin, thereby modifying constitutive signaling relevant to vascular inflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": " Finally, novel EP3 splice variants in gastric and vascular tissues as well as in tolerogenic dendritic cells (which bias IL-10 production) further underscore the receptor’s multifaceted roles in both homeostatic and pathological conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yoko Matsuoka, Tomoyuki Furuyashiki, Haruhiko Bito, et al. 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