Article (Scientific journals)
Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells
Santio, Niina M.; Landor, Sebastian K.-J.; Vahtera, Laura et al.
2016In Oncotarget, 7 (28), p. 43220-43238
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Keywords :
Animals; Breast Neoplasms/pathology; Carcinogenesis/metabolism; Cell Movement; Chick Embryo; Female; Humans; MCF-7 Cells; Male; Mice; Phosphorylation; Prostatic Neoplasms/pathology; Proto-Oncogene Proteins c-pim-1/metabolism; Receptor, Notch1/metabolism; Receptor, Notch2/metabolism; Receptor, Notch3/metabolism; Serine/metabolism; Signal Transduction; Xenograft Model Antitumor Assays; Notch1; Pim kinases; metabolism; migration; tumorigenesis
Abstract :
[en] Tumorigenesis is a multistep process involving co-operation between several deregulated oncoproteins. In this study, we unravel previously unrecognized interactions and crosstalk between Pim kinases and the Notch signaling pathway, with implications for both breast and prostate cancer. We identify Notch1 and Notch3, but not Notch2, as novel Pim substrates and demonstrate that for Notch1, the serine residue 2152 is phosphorylated by all three Pim family kinases. This target site is located in the second nuclear localization sequence (NLS) of the Notch1 intracellular domain (N1ICD), and is shown to be important for both nuclear localization and transcriptional activity of N1ICD. Phosphorylation-dependent stimulation of Notch1 signaling promotes migration of prostate cancer cells, balances glucose metabolism in breast cancer cells, and supports in vivo growth of both types of cancer cells on chick embryo chorioallantoic membranes. Furthermore, Pim-induced growth of orthotopic prostate xenografts in mice is associated with enhanced nuclear Notch1 activity. Finally, simultaneous inhibition of Pim and Notch abrogates the cellular responses more efficiently than individual treatments, opening up new vistas for combinatorial cancer therapy.
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Author, co-author :
Santio, Niina M.;  University of Turku
Landor, Sebastian K.-J.;  Karolinska Institutet
Vahtera, Laura;  University of Turku
Yla-Pelto, Jani;  University of Turku
Paloniemi, Elina;  Turku University of Applied Sciences
Imanishi, Susumu Y.;  Turku Centre for Biotechnology
Corthals, Garry;  Turku Centre for Biotechnology
Varjosalo, Markku;  University of Helsinki
Manoharan, Ganesh Babu ;  University of Tartu
Uri, Asko;  University of Tartu
Lendahl, Urban;  Karolinska Institutet
Sahlgren, Cecilia;  Turku Centre for Biotechnology
Koskinen, Paivi J.;  University of Turku
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Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells
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Impact Journals, United States - New York
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