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Fusion tyrosine kinase NPM-ALK Deregulates MSH2 and suppresses DNA mismatch repair function novel insights into a potent oncoprotein. Am J Pathol 2011 Jul;179(1):411-21

Date

06/28/2011

Pubmed ID

21703420

Pubmed Central ID

PMC3123797

DOI

10.1016/j.ajpath.2011.03.045

Scopus ID

2-s2.0-80052489979 (requires institutional sign-in at Scopus site)   13 Citations

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.

Author List

Young LC, Bone KM, Wang P, Wu F, Adam BA, Hegazy S, Gelebart P, Holovati J, Li L, Andrew SE, Lai R

Author

Kathleen M. Bone PhD Associate Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

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