{"id":107428,"date":"2023-06-14T16:03:24","date_gmt":"2023-06-14T20:03:24","guid":{"rendered":"https:\/\/med.virginia.edu\/cell-biology\/?p=107428"},"modified":"2025-05-15T11:37:07","modified_gmt":"2025-05-15T15:37:07","slug":"connexin-37-sequestering-of-activated-erk-in-the-cytoplasm-promotes-p27-mediated-endothelial-cell-cycle-arrest","status":"publish","type":"post","link":"https:\/\/med.virginia.edu\/cell-biology\/2023\/06\/14\/connexin-37-sequestering-of-activated-erk-in-the-cytoplasm-promotes-p27-mediated-endothelial-cell-cycle-arrest\/","title":{"rendered":"Connexin 37 sequestering of activated-ERK in the cytoplasm promotes p27-mediated endothelial cell cycle arrest"},"content":{"rendered":"

UVA Author:<\/strong> Nicholas Chavkin
\nCitation:<\/strong> Acharya BR, Fang JS, Jeffery ED, Chavkin NW, Genet G, Vasavada H, Nelson EA, Sheynkman GM, Humphries MJ, Hirschi KK. Connexin 37 sequestering of activated-ERK in the cytoplasm promotes p27-mediated endothelial cell cycle arrest. Life Sci Alliance. 2023 May 17;6(8):e202201685. doi: 10.26508\/lsa.202201685. PMID: 37197981; PMCID: PMC10192821.<\/p>\n

DOI:<\/strong> https:\/\/doi.org\/10.26508\/lsa.202201685<\/a>
\nPub-Med Number<\/strong>: 37197981<\/p>\n

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\n
\n

Connexin37-mediated regulation of cell cycle modulators and, consequently, growth arrest lack mechanistic understanding. We previously showed that arterial shear stress up-regulates Cx37 in endothelial cells and activates a Notch\/Cx37\/p27 signaling axis to promote G1 cell cycle arrest, and this is required to enable arterial gene expression. However, how induced expression of a gap junction protein, Cx37, up-regulates cyclin-dependent kinase inhibitor p27 to enable endothelial growth suppression and arterial specification is unclear. Herein, we fill this knowledge gap by expressing wild-type and regulatory domain mutants of Cx37 in cultured endothelial cells expressing the Fucci cell cycle reporter. We determined that both the channel-forming and cytoplasmic tail domains of Cx37 are required for p27 up-regulation and late G1 arrest. Mechanistically, the cytoplasmic tail domain of Cx37 interacts with, and sequesters, activated ERK in the cytoplasm. This then stabilizes pERK nuclear target Foxo3a, which up-regulates p27 transcription. Consistent with previous studies, we found this Cx37\/pERK\/Foxo3a\/p27 signaling axis functions downstream of arterial shear stress to promote endothelial late G1 state and enable up-regulation of arterial genes.<\/p>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

UVA Author: Nicholas Chavkin Citation: Acharya BR, Fang JS, Jeffery ED, Chavkin NW, Genet G, Vasavada H, Nelson EA, Sheynkman GM, Humphries MJ, Hirschi KK. Connexin 37 sequestering of activated-ERK in the cytoplasm promotes p27-mediated endothelial cell cycle arrest. Life Sci Alliance. 2023 May 17;6(8):e202201685. doi: 10.26508\/lsa.202201685. PMID: 37197981; PMCID: PMC10192821. DOI: https:\/\/doi.org\/10.26508\/lsa.202201685 Pub-Med Number: […]<\/p>\n","protected":false},"author":1740,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":"","_links_to":"","_links_to_target":""},"categories":[13],"tags":[],"class_list":["post-107428","post","type-post","status-publish","format-standard","hentry","category-featured-publications"],"acf":false,"yoast_head":"\nConnexin 37 sequestering of activated-ERK in the cytoplasm promotes p27-mediated endothelial cell cycle arrest - Department of Cell Biology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/med.virginia.edu\/cell-biology\/2023\/06\/14\/connexin-37-sequestering-of-activated-erk-in-the-cytoplasm-promotes-p27-mediated-endothelial-cell-cycle-arrest\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Connexin 37 sequestering of activated-ERK in the cytoplasm promotes p27-mediated endothelial cell cycle arrest - Department of Cell Biology\" \/>\n<meta property=\"og:description\" content=\"UVA Author: Nicholas Chavkin Citation: Acharya BR, Fang JS, Jeffery ED, Chavkin NW, Genet G, Vasavada H, Nelson EA, Sheynkman GM, Humphries MJ, Hirschi KK. Connexin 37 sequestering of activated-ERK in the cytoplasm promotes p27-mediated endothelial cell cycle arrest. Life Sci Alliance. 2023 May 17;6(8):e202201685. doi: 10.26508\/lsa.202201685. PMID: 37197981; PMCID: PMC10192821. 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