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K-Ras(V12) differentially affects the three Akt isoforms in lung and pancreatic carcinoma cells and upregulates E-cadherin and NCAM via Akt3

التفاصيل البيبلوغرافية
العنوان: K-Ras(V12) differentially affects the three Akt isoforms in lung and pancreatic carcinoma cells and upregulates E-cadherin and NCAM via Akt3
المؤلفون: Rebekka Geißert, Angela Lammert, Stefanie Wirth, Rabea Hönig, Dirk Lohfink, Monika Unger, Denis Pek, Konstantin Schlüter, Theresa Scheftschik, Daniel J. Smit, Manfred Jücker, Andre Menke, Klaudia Giehl
المصدر: Cell Communication and Signaling, Vol 22, Iss 1, Pp 1-23 (2024)
بيانات النشر: BMC, 2024.
سنة النشر: 2024
المجموعة: LCC:Medicine
LCC:Cytology
مصطلحات موضوعية: K-Ras, PI3-kinase, PKB/Akt isoforms, Akt3, E-cadherin, NCAM, Medicine, Cytology, QH573-671
الوصف: Abstract K-Ras is the most frequently mutated Ras variant in pancreatic, colon and non-small cell lung adenocarcinoma. Activating mutations in K-Ras result in increased amounts of active Ras-GTP and subsequently a hyperactivation of effector proteins and downstream signaling pathways. Here, we demonstrate that oncogenic K-Ras(V12) regulates tumor cell migration by activating the phosphatidylinositol 3-kinases (PI3-K)/Akt pathway and induces the expression of E-cadherin and neural cell adhesion molecule (NCAM) by upregulation of Akt3. In vitro interaction and co-precipitation assays identified PI3-Kα as a bona fide effector of active K-Ras4B but not of H-Ras or N-Ras, resulting in enhanced Akt phosphorylation. Moreover, K-Ras(V12)-induced PI3-K/Akt activation enhanced migration in all analyzed cell lines. Interestingly, Western blot analyses with Akt isoform-specific antibodies as well as qPCR studies revealed, that the amount and the activity of Akt3 was markedly increased whereas the amount of Akt1 and Akt2 was downregulated in EGFP-K-Ras(V12)-expressing cell clones. To investigate the functional role of each Akt isoform and a possible crosstalk of the isoforms in more detail, each isoform was stably depleted in PANC-1 pancreatic and H23 lung carcinoma cells. Akt3, the least expressed Akt isoform in most cell lines, is especially upregulated and active in Akt2-depleted cells. Since expression of EGFP-K-Ras(V12) reduced E-cadherin-mediated cell-cell adhesion by induction of polysialylated NCAM, Akt3 was analyzed as regulator of E-cadherin and NCAM. Western blot analyses revealed pronounced reduction of E-cadherin and NCAM in the Akt3-kd cells, whereas Akt1 and Akt2 depletion upregulated E-cadherin, especially in H23 lung carcinoma cells. In summary, we identified oncogenic K-Ras4B as a key regulator of PI3-Kα-Akt signaling and Akt3 as a crucial regulator of K-Ras4B-induced modulation of E-cadherin and NCAM expression and localization.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1478-811X
Relation: https://doaj.org/toc/1478-811X
DOI: 10.1186/s12964-024-01484-2
URL الوصول: https://doaj.org/article/6ad39e31b6e94163a40b075a091f8050
رقم الأكسشن: edsdoj.6ad39e31b6e94163a40b075a091f8050
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:1478811X
DOI:10.1186/s12964-024-01484-2