Fusion tyrosine kinase NPM-ALK Deregulates MSH2 and suppresses DNA mismatch repair function novel insights into a potent oncoprotein.

Abstract

The fusion tyrosine kinase NPM-ALK is central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK(+)ALCL). We recently identified that MSH2, a key DNA mismatch repair (MMR) protein integral to the suppression of tumorigenesis, is an NPM-ALK-interacting protein. In this study, we found in vitro evidence that enforced expression of NPM-ALK in HEK293 cells suppressed MMR function. Correlating with these findings, six of nine ALK(+)ALCL tumors displayed evidence of microsatellite instability, as opposed to none of the eight normal DNA control samples (P = 0.007, Student's t-test). Using co-immunoprecipitation, we found that increasing levels of NPM-ALK expression in HEK293 cells resulted in decreased levels of MSH6 bound to MSH2, whereas MSH2·NPM-ALK binding was increased. The NPM-ALK·MSH2 interaction was dependent on the activation/autophosphorylation of NPM-ALK, and the Y191 residue of NPM-ALK was a crucial site for this interaction and NPM-ALK-mediated MMR suppression. MSH2 was found to be tyrosine phosphorylated in the presence of NPM-ALK. Finally, NPM-ALK impeded the expected DNA damage-induced translocation of MSH2 out of the cytoplasm. To conclude, our data support a model in which the suppression of MMR by NPM-ALK is attributed to its ability to interfere with normal MSH2 biochemistry and function.

• Authors: Leah C Young, Kathleen M Bone, Peng Wang, Fang Wu, Benjamin A Adam, Samar Hegazy, Pascal Gelebart, Jelena Holovati, Liang Li, Susan E Andrew, Raymond Lai
• Journal: The American journal of pathology (Am J Pathol) Vol. 179 Issue 1 Pg. 411-21 (Jul 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21703420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• G-T mismatch-binding protein
• Tyrosine
• p80(NPM-ALK) protein
• Protein-Tyrosine Kinases
• MSH2 protein, human
• MutS Homolog 2 Protein

Topics

• Cytoplasm (metabolism)
• DNA Damage
• DNA Mismatch Repair
• DNA-Binding Proteins (genetics, metabolism)
• Humans
• Immunoenzyme Techniques
• Immunoprecipitation
• Lymphoma, Large B-Cell, Diffuse (genetics, metabolism, pathology)
• Lymphoma, Large-Cell, Anaplastic (genetics, metabolism, pathology)
• Microsatellite Instability
• MutS Homolog 2 Protein (genetics, metabolism)
• Phosphorylation
• Protein Multimerization
• Protein Transport
• Protein-Tyrosine Kinases (genetics, metabolism)
• Tumor Cells, Cultured
• Tyrosine (metabolism)