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

N.M. Santio, S.K.-J. Landor, L. Vahtera, J. Ylä-Pelto, E. Paloniemi, S.Y. Imanishi, G. Corthals, M. Varjosalo, G.B. Manoharan, A. Uri, U. Lendahl, C.M. Sahlgren, P.J. Koskinen

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Abstract

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.

Original languageEnglish
Pages (from-to)43220-43238
Number of pages19
JournalOncotarget
Volume7
Issue number28
Early online date7 May 2016
DOIs
Publication statusPublished - 12 Jul 2016

Keywords

  • Metabolism
  • Migration
  • Notch1
  • Pim kinases
  • Tumorigenesis
  • Phosphorylation
  • Breast Neoplasms/pathology
  • Signal Transduction
  • Humans
  • Serine/metabolism
  • Male
  • Carcinogenesis/metabolism
  • Receptor, Notch2/metabolism
  • Chick Embryo
  • Xenograft Model Antitumor Assays
  • Animals
  • MCF-7 Cells
  • Prostatic Neoplasms/pathology
  • Receptor, Notch3/metabolism
  • Female
  • Proto-Oncogene Proteins c-pim-1/metabolism
  • Mice
  • Receptor, Notch1/metabolism
  • Cell Movement
  • tumorigenesis
  • migration
  • metabolism

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  • Cite this

    Santio, N. M., Landor, SK-J., Vahtera, L., Ylä-Pelto, J., Paloniemi, E., Imanishi, S. Y., Corthals, G., Varjosalo, M., Manoharan, G. B., Uri, A., Lendahl, U., Sahlgren, C. M., & Koskinen, P. J. (2016). Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells. Oncotarget, 7(28), 43220-43238. https://doi.org/10.18632/oncotarget.9215