Reference : Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and p...
Scientific journals : Article
Human health sciences : Oncology
Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells
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 mailto [University of Tartu]
Uri, Asko [University of Tartu]
Lendahl, Urban [Karolinska Institutet]
Sahlgren, Cecilia [Turku Centre for Biotechnology]
Koskinen, Paivi J. [University of Turku]
United States
[en] 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
[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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