{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nVEPH1, the mammalian ortholog of the Drosophila protein Melted, has emerged as a critical modulator of cellular growth and differentiation pathways. In ovarian cancer cells, elevated VEPH1 expression alters transcriptional programs associated with metabolism, FOXO, and Hippo signaling, and exerts a repressive effect on transforming growth factor‑β (TGF‑β) signaling by interacting with the TGF‑β receptor I (TβRI). This interaction impedes the release and subsequent nuclear accumulation of activated SMAD2, thereby reducing canonical TGF‑β–mediated transcriptional responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its modulation of TGF‑β signaling, VEPH1 is found to be amplified in several human cancers, including ovarian neoplasms, suggesting that its altered expression may be functionally linked to tumor progression. Although its precise impact on oncogenic processes remains to be fully defined, the inhibition of TGF‑β signaling by VEPH1 raises the possibility that it may influence the balance between proliferative and growth‐suppressive pathways during cancer development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cancer, recent studies have demonstrated that VEPH1 plays a role in vascular pathophysiology. In models of abdominal aortic aneurysm, angiotensin II–induced upregulation of VEPH1 in aortic smooth muscle cells promotes a phenotypic switch from a contractile to a synthetic/dedifferentiated state. This is accompanied by the suppression of TGF‑β1/Smad3 signaling, suggesting that VEPH1 elevation contributes to adverse vascular remodeling and could represent a pathogenic factor in aneurysm formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, in hepatocellular carcinoma, VEPH1 has been identified as a novel tumor suppressor acting through the mechanistic target of rapamycin complex 1 (mTORC1) axis. Abnormal activation of mTORC1 is a frequent feature in liver cancer, and VEPH1 appears to mitigate this pathogenic signaling, thereby restraining tumor progression. Collectively, these findings highlight VEPH1 as a multifaceted regulator that modulates key signaling pathways—including TGF‑β, mTORC1, and others—in development, cancer, and vascular disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Premalatha Shathasivam, Alexandra Kollara, Maurice J Ringuette, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human ortholog of Drosophila Melted impedes SMAD2 release from TGF-β receptor I to inhibit TGF-β signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1504671112"}], "href": "https://doi.org/10.1073/pnas.1504671112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26039994"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26039994"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Premalatha Shathasivam, Alexandra Kollara, Thomasina Spybey, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VEPH1 expression decreases vascularisation in ovarian cancer xenografts and inhibits VEGFA and IL8 expression through inhibition of AKT activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/bjc.2017.51"}], "href": "https://doi.org/10.1038/bjc.2017.51"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28301874"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28301874"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiaofeng Shi, Caiming Xu, Yongqi Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel role of VEPH1 in regulating AoSMC phenotypic switching."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.29736"}], "href": "https://doi.org/10.1002/jcp.29736"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32342520"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32342520"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Pingping Dong, Xiaoxiao Wang, Longzi Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dampened VEPH1 activates mTORC1 signaling by weakening the TSC1/TSC2 association in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hepatol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jhep.2020.06.027"}], "href": "https://doi.org/10.1016/j.jhep.2020.06.027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32610114"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32610114"}]}]}]}