Disheveled proteins promote cell growth and tumorigenicity in ALK-positive anaplastic large cell lymphoma

Autor: Pascal Gelebart, Robert J. Ingham, Mona Anand, Abdulraheem Alshareef, Raymond Lai, Hanan Armanious, Samar A. Hegazy
Rok vydání: 2012
Předmět:
Dishevelled Proteins
Biology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
hemic and lymphatic diseases
Cell Line
Tumor
medicine
Anaplastic lymphoma kinase
Humans
Anaplastic Lymphoma Kinase
Phosphorylation
RNA
Small Interfering
Anaplastic large-cell lymphoma
beta Catenin
030304 developmental biology
Adaptor Proteins
Signal Transducing
Cell Proliferation
0303 health sciences
NFATC Transcription Factors
Cell growth
Wnt signaling pathway
Receptor Protein-Tyrosine Kinases
Tyrosine phosphorylation
Cell Biology
Protein-Tyrosine Kinases
medicine.disease
Phosphoproteins
Cell biology
Wnt Proteins
src-Family Kinases
chemistry
030220 oncology & carcinogenesis
Lymphoma
Large-Cell
Anaplastic
RNA Interference
Signal transduction
Tyrosine kinase
Proto-oncogene tyrosine-protein kinase Src
Zdroj: Cellular signalling. 25(1)
ISSN: 1873-3913
Popis: Our previous oligonucleotide array studies revealed that ALK-positive anaplastic large cell lymphoma (ALK + ALCL) express high levels of the disheveled proteins (Dvls), a family of proteins that is integral to the Wnt signaling pathways. In this study, we assessed whether the Dvls are important in the pathogenesis of ALK + ALCL. By Western blotting, Dvl-2 and Dvl-3 were found to be highly expressed in ALK + ALCL cell lines and patient samples. The higher molecular weight forms, consistent with phosphorylated/active Dvl proteins, were observed in these lysates. siRNA knock-down of Dvls did not affect the Wnt canonical pathway, as assessed by the β-catenin protein levels and nuclear localization. In contrast, the same treatment led to changes in the transcriptional activity of NFAT and the phosphorylation status of Src, both of which are known to be regulated by the Wnt non-canonical signaling pathways in other cell types. Coupled with these biochemical changes, there was a significant decrease in cell growth and soft agar colony formation. NPM-ALK, the oncogenic tyrosine kinase characteristic of ALK + ALCL, was found to bind to the Dvls and enhance their tyrosine phosphorylation. In conclusion, our data suggest that the Dvls contribute to the pathogenesis of ALK + ALCL via signaling in the Wnt non-canonical pathways. To our knowledge, this is the first report demonstrating a physical and functional interaction between the Dvls and an oncogenic tyrosine kinase.
Databáze: OpenAIRE
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