{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPhospholipase D1 (PLD1) is emerging as a central mediator of oncogenic and survival‐promoting signals in cancer cells. Elevated PLD1 activity can generate phosphatidic acid (PA) that activates mammalian target of rapamycin (mTOR) signaling, thereby conferring rapamycin resistance and promoting cell cycle progression and survival. Indeed, breast cancer cells with high PLD1 activity are resistant to rapamycin‐mediated growth arrest, and PLD1 is required for the activation of upstream regulators such as Rheb and for amino acid–induced mTORC1 stimulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nApart from its tumor cell–intrinsic functions, PLD1 in the tumor microenvironment promotes neovascularization and metastasis. Deficiency or pharmacological inhibition of PLD1 in stromal cells blunts vascular endothelial growth factor–mediated Akt and MAPK signaling, reducing endothelial cell adhesion, migration, and ultimately tumor growth and metastatic seeding."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn neuronal settings, PLD1 modulates amyloidogenic processing; interaction with presenilin 1 recruits PLD1 to the Golgi/trans‐Golgi network, thereby suppressing γ‐secretase activity and lowering β‐amyloid production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPLD1 activity is also integrated with actin dynamics. Phosphorylated cofilin, traditionally thought to be inactive, directly interacts with and stimulates PLD1 to promote downstream effects including actin stress fiber formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn immune cells, PLD1 contributes to cell motility. Depletion of PLD1 in leukocytes abolishes basal chemokinesis and impairs chemotactic responses, underlining its role in regulating the cytoskeletal reorganizations required for directed migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, in bronchial epithelial cells, activation of PLD1 by sphingosine 1‐phosphate initiates ERK phosphorylation cascades that culminate in interleukin‑8 secretion, linking PLD1 to inflammatory responses in the airways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPLD1 also plays a role in host–pathogen interactions. In lung epithelial cells, β‑1,3‑glucan from germinated Aspergillus fumigatus activates PLD1, which is necessary for efficient fungal internalization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn vascular endothelium, PLD1 is selectively involved in the regulated secretion of von Willebrand factor, underscoring its role in hemostatic balance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUpstream regulators, notably Rho family GTPases, modulate PLD1 activity through specific interactions; for example, a key residue in Cdc42’s insert helix is critical for the GTP‐dependent activation of PLD1, emphasizing the isoform‑specific engagement by small GTPases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn reproductive physiology, PLD1 activation via protein kinase C (PKC) by diacylglycerol has been shown to trigger acrosomal exocytosis in human sperm, an essential step in fertilization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the post‑translational level, PLD1 is regulated by multi‑monoubiquitination, which impacts its subcellular localization and turnover, revealing a novel mechanism of PLD1 regulation that influences its signaling output."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn endometrial carcinomas, elevated PLD1 expression is associated with an aberrant nuclear accumulation of active mTOR complex 2 components, further linking PLD1 to tumorigenic signaling pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPLD1 also impacts anti‑apoptotic mechanisms by upregulating Bcl‑2 expression via activation of STAT3, thereby contributing to survival signals that favor oncogenic transformation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, PLD1 serves as a nexus for nutrient sensing by integrating signals from growth factors and amino acids to modulate mTORC1 activity through its PA‐producing function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn ocular tissues, particularly the retinal pigment epithelium, PLD1 (in conjunction with PLD2) contributes to the inflammatory response by modulating COX‑2 expression and ERK1/2 signaling, which may have implications for inflammatory retinal diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of gastrointestinal malignancies, loss of the microRNA miR‑638 leads to derepression of PLD1, and the resultant PLD1 overexpression promotes tumor cell proliferation, highlighting its potential as a prognostic biomarker and therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, PLD1 activity enhances the stabilization of hypoxia‑inducible factor‑1α (HIF‑1α) and increases vascular endothelial growth factor secretion, processes that further drive tumor angiogenesis and progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent studies also implicate PLD1 in metabolic plasticity; by promoting autophagic lipid hydrolysis, PLD1 helps fuel fatty acid oxidation and maintain ATP production, thus supporting cancer cell survival under metabolic stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, in hepatic stellate cells, PLD1‐driven autophagy regulates type I collagen accumulation, suggesting that PLD1 may influence fibrogenic responses in chronic liver disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yuhong Chen, Yang Zheng, David A Foster "}, {"type": "b", "children": [{"type": "t", "text": "Phospholipase D confers rapamycin resistance in human breast cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1206565"}], "href": "https://doi.org/10.1038/sj.onc.1206565"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12813467"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12813467"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Y Sun, Y Fang, M-S Yoon, et al. 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