TY - JOUR
T1 - Disheveled proteins promote cell growth and tumorigenicity in ALK-positive anaplastic large cell lymphoma
AU - Hegazy, Samar A.
AU - Alshareef, Abdulraheem
AU - Gelebart, Pascal
AU - Anand, Mona
AU - Armanious, Hanan
AU - Ingham, Robert J.
AU - Lai, Raymond
N1 - Funding Information:
S.H. is a graduate student supported by an Egyptian governmental doctoral scholarship and the Queen Elisabeth II graduate scholarship administered by the University of Alberta. Abdulraheem Alshareef is a graduate student sponsored by Taibah University, Al Madina Al Munawarrah, Saudi Arabia. This study is supported by operating research grants from the Canadian Institute of Health Research and Alberta Cancer Foundation awarded to R.L.
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
KW - Anaplastic large cell lymphoma
KW - Disheveled proteins
KW - NPM-ALK
KW - Wnt signaling pathways
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U2 - 10.1016/j.cellsig.2012.09.027
DO - 10.1016/j.cellsig.2012.09.027
M3 - Article
C2 - 23022960
AN - SCOPUS:84868308598
SN - 0898-6568
VL - 25
SP - 295
EP - 307
JO - Cellular Signalling
JF - Cellular Signalling
IS - 1
ER -