The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling

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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00147-14.

ACKNOWLEDGMENTS

We thank the Hollings Cancer Center Cell Evaluation and Therapy Shared Resource and Biorepository and Tissue Analysis Shared Resource at MUSC for providing excellent support of this project. Paul J. Coffer (Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands) kindly provided FLAG-tagged eIF4B expression plasmids. We thank Scott D. Cramer (University of Colorado School of Medicine) for sharing the mouse prostate epithelial cells expressing Pim-1. We are grateful to GlaxoSmithKline for supplying GSK690693. We thank Marina Konopleva and Juliana Benito (M. D. Anderson Cancer Center) for providing AML cell lines Molm-16 and OCI-AML2.

This work is supported by NIH grants 1K01DK085196 (to B.C.), 1R01CA173200 (to A.S.K.), and W81XWH-12-10560 (to A.S.K.) and the HCC support grant 5P30CA138313. This work was funded by a Conquer Cancer Foundation of ASCO Young Investigator Award (to A.M.).

Any opinions, findings, and conclusions expressed in this material are those of the authors and do not necessarily reflect those of the American Society of Clinical Oncology or the Conquer Cancer Foundation.

We declare no potential conflicts of interest.