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

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

Fingerprint

Proto-Oncogene Proteins c-pim-1
Proto-Oncogene Proteins c-met
Protein Kinases
Eukaryotic Initiation Factors
Neoplasms
Cell Movement
Phosphorylation
Clinical Trials, Phase I
Hepatocyte Growth Factor
Tumor Cell Line
Knockout Mice
Small Interfering RNA
Bone Marrow

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Cen, B., Xiong, Y., Song, J. H., Mahajan, S., DuPont, R., McEachern, K., ... 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

The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling. / Cen, Bo; Xiong, Ying; Song, Jin H.; Mahajan, Sandeep; DuPont, Rachel; McEachern, Kristen; DeAngelo, Daniel J.; Cortes, Jorge E.; Minden, Mark D.; Ebens, Allen; Mims, Alice; LaRue, Amanda C.; Kraft, Andrew S.

In: Molecular and Cellular Biology, Vol. 34, No. 13, 07.2014, p. 2517-2532.

Research output: Contribution to journalArticle

Cen, B, Xiong, Y, Song, JH, Mahajan, S, DuPont, R, McEachern, K, DeAngelo, DJ, Cortes, JE, Minden, MD, Ebens, A, Mims, A, LaRue, AC & Kraft, AS 2014, 'The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling', Molecular and Cellular Biology, vol. 34, no. 13, pp. 2517-2532. https://doi.org/10.1128/MCB.00147-14
Cen, Bo ; Xiong, Ying ; Song, Jin H. ; Mahajan, Sandeep ; DuPont, Rachel ; McEachern, Kristen ; DeAngelo, Daniel J. ; Cortes, Jorge E. ; Minden, Mark D. ; Ebens, Allen ; Mims, Alice ; LaRue, Amanda C. ; Kraft, Andrew S. / The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling. In: Molecular and Cellular Biology. 2014 ; Vol. 34, No. 13. pp. 2517-2532.
@article{5f3018a3f9d04674b729c0cc9de601d6,
title = "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.",
author = "Bo Cen and Ying Xiong and Song, {Jin H.} and Sandeep Mahajan and Rachel DuPont and Kristen McEachern and DeAngelo, {Daniel J.} and Cortes, {Jorge E.} and Minden, {Mark D.} and Allen Ebens and Alice Mims and LaRue, {Amanda C.} and Kraft, {Andrew S.}",
year = "2014",
month = "7",
doi = "10.1128/MCB.00147-14",
language = "English (US)",
volume = "34",
pages = "2517--2532",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "13",

}

TY - JOUR

T1 - The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling

AU - Cen, Bo

AU - Xiong, Ying

AU - Song, Jin H.

AU - Mahajan, Sandeep

AU - DuPont, Rachel

AU - McEachern, Kristen

AU - DeAngelo, Daniel J.

AU - Cortes, Jorge E.

AU - Minden, Mark D.

AU - Ebens, Allen

AU - Mims, Alice

AU - LaRue, Amanda C.

AU - Kraft, Andrew S.

PY - 2014/7

Y1 - 2014/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84901797578&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901797578&partnerID=8YFLogxK

U2 - 10.1128/MCB.00147-14

DO - 10.1128/MCB.00147-14

M3 - Article

C2 - 24777602

AN - SCOPUS:84901797578

VL - 34

SP - 2517

EP - 2532

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 13

ER -