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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3907-3916.
Prepublished online as a Blood First Edition Paper on August 16, 2005; DOI 10.1182/blood-2005-03-1204.
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NEOPLASIA
p130Cas mediates the transforming properties of the anaplastic lymphoma kinase
Chiara Ambrogio,
Claudia Voena,
Andrea D. Manazza,
Roberto Piva,
Ludovica Riera,
Laura Barberis,
Carlotta Costa,
Guido Tarone,
Paola Defilippi,
Emilio Hirsch,
Elisabetta Boeri Erba,
Shabaz Mohammed,
Ole N. Jensen,
Giorgio Palestro,
Giorgio Inghirami, and
Roberto Chiarle
From the Center for Experimental Research and Medical Studies (CERMS) and the Departments of Biomedical Sciences and Human Oncology and of Genetics, Biology, and Biochemistry, University of Turin, Turin, Italy; and the Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Translocations of the anaplastic lymphoma kinase (ALK) gene have been described in anaplastic large-cell lymphomas (ALCLs) and in stromal tumors. The most frequent translocation, t(2;5), generates the fusion protein nucleophosmin (NPM)–ALK with intrinsic tyrosine kinase activity. Along with transformation, NPM-ALK induces morphologic changes in fibroblasts and lymphoid cells, suggesting a direct role of ALK in cell shaping. In this study, we used a mass-spectrometry–based proteomic approach to search for proteins involved in cytoskeleton remodeling and identified p130Cas (p130 Crk-associated substrate) as a novel interactor of NPM-ALK. In 293 cells and in fibroblasts as well as in human ALK-positive lymphoma cell lines, NPM-ALK was able to bind p130Cas and to induce its phosphorylation. Both of the effects were dependent on ALK kinase activity and on the adaptor protein growth factor receptor–bound protein 2 (Grb2), since no binding or phosphorylation was found with the kinase-dead mutant NPM-ALKK210R or in the presence of a Grb2 dominant-negative protein. Phosphorylation of p130Cas by NPM-ALK was partially independent from Src (tyrosine kinase pp60c-src) kinase activity, as it was still detectable in Syf-/- cells. Finally, p130Cas-/- (also known as Bcar1-/-) fibroblasts expressing NPM-ALK showed impaired actin filament depolymerization and were no longer transformed compared with wild-type cells, indicating an essential role of p130Cas activation in ALK-mediated transformation.
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