{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe prolactin receptor (PRLR) is a multifunctional cytokine receptor that governs a wide variety of physiological processes. In adipose tissue during lactation, for example, PRLR activation directly down‐regulates lipoprotein lipase activity to help redistribute nutrients."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, the immune system expresses multiple PRLR isoforms with distinct ligand affinities and signaling kinetics that enable prolactin to modulate diverse cytokine‐activated pathways (e.g. via Jak2, STAT5, and other mediators) to fine‐tune immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn reproductive tissues, PRLR signaling plays a critical role in breast and gonadal physiology. In breast epithelial cells, estradiol up‐regulates transcription of the PRLR gene to promote differentiation through the long receptor isoform’s activation of the Jak2/STAT5 cascade, whereas selective expression of short PRLR forms can dampen this signal."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, in human spermatozoa, activation of PRLR triggers prosurvival signaling pathways—including Akt phosphorylation—that preserve motility and integrity, while mutations in PRLR have been linked to familial hyperprolactinemia by disrupting normal receptor signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " The PRLR system is also implicated in bone and cartilage formation, where its expression in mesenchymal tissues supports tissue repair processes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and in brain regions—via neuronal PRLR isoforms—that regulate maternal behavior and energy homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, extrapituitary functions of prolactin, such as in trophoblasts, coupled with roles in pancreatic β‐cell expansion during pregnancy, further underscore the receptor’s broad regulatory influence on reproduction and metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant PRLR signaling has been increasingly implicated in breast cancer pathogenesis. Enhanced activation of PRLR—whether through overexpression, failure of normal ligand‐induced receptor turnover, or constitutive gain‐of‐function mutations—can augment proliferation, invasiveness, and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": " Detailed structural studies have revealed that motifs such as the conserved WSXWS sequence underpin receptor dimerization and activation, providing a molecular basis for the design of potent PRLR antagonists."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "18"}]}, {"type": "t", "text": " In addition, crosstalk between PRLR and receptors such as the growth hormone receptor—via heterodimerization—further modulates breast cancer cell signaling, and lower PRLR expression in invasive tumors has been associated with a more favorable prognosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Charlotte Ling, Louise Svensson, Birgitta Odén, et al. 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