Research Papers:

Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells

Niina M. Santio, Sebastian K.J. Landor, Laura Vahtera, Jani Ylä-Pelto, Elina Paloniemi, Susumu Y. Imanishi, Garry Corthals, Markku Varjosalo, Ganesh Babu Manoharan, Asko Uri, Urban Lendahl, Cecilia Sahlgren _ and Päivi J. Koskinen

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Oncotarget. 2016; 7:43220-43238. https://doi.org/10.18632/oncotarget.9215

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Niina M. Santio1,2,*, Sebastian K.-J. Landor3,4,*, Laura Vahtera1, Jani Ylä-Pelto1,2, Elina Paloniemi5, Susumu Y. Imanishi3,9, Garry Corthals3,10, Markku Varjosalo6, Ganesh Babu Manoharan7, Asko Uri7, Urban Lendahl4, Cecilia Sahlgren3,8, Päivi J. Koskinen1

1Section of Genetics and Physiology, Department of Biology, University of Turku, Turku, Finland

2Drug Research Doctoral Programme, University of Turku, Turku, Finland

3Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland

4Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

5Turku University of Applied Sciences, Turku, Finland

6Institute of Biotechnology, University of Helsinki, Helsinki, Finland

7Institute of Chemistry, University of Tartu, Tartu, Estonia

8Department of Biomedical Engineering, Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands

9Current address: Faculty of Pharmacy, Meijo University, Nagoya, Japan

10Current address: Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands

*These authors have contributed equally to this work

Correspondence to:

Cecilia Sahlgren, email: cecilia.sahlgren@btk.fi

Päivi J. Koskinen, email: paivi.koskinen@utu.fi

Keywords: Notch1, Pim kinases, migration, metabolism, tumorigenesis

Received: October 14, 2015     Accepted: April 23, 2016     Published: May 07, 2016


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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