Functional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphoma

Bojie Dai, X. Frank Zhao, Krystyna Mazan-Mamczarz, Patrick Hagner, Sharon Corl, El Mustapha Bahassi, Song Lu, Peter J. Stambrook, Paul Shapiro and Ronald B. Gartenhaus ()
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Bojie Dai: University of Maryland, Marlene & Stewart Greenebaum Cancer Center
X. Frank Zhao: University of Maryland School of Medicine
Krystyna Mazan-Mamczarz: University of Maryland, Marlene & Stewart Greenebaum Cancer Center
Patrick Hagner: University of Maryland, Marlene & Stewart Greenebaum Cancer Center
Sharon Corl: University of Maryland, Marlene & Stewart Greenebaum Cancer Center
El Mustapha Bahassi: University of Cincinnati
Song Lu: University of Maryland School of Medicine
Peter J. Stambrook: University of Cincinnati
Paul Shapiro: University of Maryland School of Pharmacy
Ronald B. Gartenhaus: University of Maryland, Marlene & Stewart Greenebaum Cancer Center

Nature Communications, 2011, vol. 2, issue 1, 1-9

Abstract: Abstract Distinct oncogenic signalling cascades have been associated with non-Hodgkin lymphoma. ERK1/2 signalling elicits both transcriptional and post-transcriptional effects through phosphorylation of numerous substrates. Here we report a novel molecular relationship between ERK1/2 and CHK2, a protein kinase that is a key mediator of the DNA damage checkpoint that responds to DNA double-strand breaks. Our studies are the first to demonstrate the co-localization and overexpression of ERK1/2 and CHK2 in diffuse large B-cell lymphoma (DLBCL). The physical interaction between ERK and CHK2 was highly dependent on phosphorylated Thr 68 of CHK2. Concurrent administration of an ERK inhibitor enhances the antitumour activity of CHK2 inhibition in both a human DLBCL xenograft model as well as primary human DLBCL cells. Our data suggest a functional interaction between ERK and CHK2 and support the potential combined therapeutic targeting of ERK and CHK2 in human DLBCL.

Date: 2011
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DOI: 10.1038/ncomms1404

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