The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling

Bo Cen, Ying Xiong, Jin H. Song, Sandeep Mahajan, Rachel DuPont, Kristen McEachern, Daniel J. DeAngelo, Jorge E. Cortes, Mark D. Minden, Allen Ebens, Alice Mims, Amanda C. LaRue, Andrew S. Kraft

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

MET, the receptor for hepatocyte growth factor (HGF), plays an important role in signaling normal and tumor cell migration and invasion. Here, we describe a previously unrecognized mechanism that promotes MET expression in multiple tumor cell types. The levels of the Pim-1 protein kinase show a positive correlation with the levels of MET protein in human tumor cell lines and patient-derived tumor materials. Using small interfering RNA (siRNA), Pim knockout mice, small-molecule inhibitors, and overexpression of Pim-1, we confirmed this correlation and found that Pim-1 kinase activity regulates HGF-induced tumor cell migration, invasion, and cell scattering. The novel biochemical mechanism for these effects involves the ability of Pim-1 to control the translation of MET by regulating the phosphorylation of eukaryotic initiation factor 4B (eIF4B) on S406. This targeted phosphorylation is required for the binding of eIF4B to the eIF3 translation initiation complex. Importantly, Pim-1 action was validated by the evaluation of patient blood and bone marrow from a phase I clinical trial of a Pim kinase inhibitor, AZD1208. These results suggest that Pim inhibitors may have an important role in the treatment of patients where MET is driving tumor biology.

Original languageEnglish (US)
Pages (from-to)2517-2532
Number of pages16
JournalMolecular and cellular biology
Volume34
Issue number13
DOIs
StatePublished - Jul 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Cen, B., Xiong, Y., Song, J. H., Mahajan, S., DuPont, R., McEachern, K., DeAngelo, D. J., Cortes, J. E., Minden, M. D., Ebens, A., Mims, A., LaRue, A. C., & Kraft, A. S. (2014). The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling. Molecular and cellular biology, 34(13), 2517-2532. https://doi.org/10.1128/MCB.00147-14