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Ambrogio, Chiara; Voena, Claudia; Manazza, Andrea D.; Piva, Roberto; Riera, Ludovica; Barberis, Laura; Costa, Carlotta; Tarone, Guido; Defilippi, Paola; Hirsch, Emilio; Erba, Elisabetta Boeri; Mohammed, Shabaz; Jensen, Ole N.; Palestro, Giorgio; Inghirami, Giorgio; Chiarle, Roberto

p130Cas mediates the transforming properties of the anaplastic lymphoma kinase

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  • Media type: E-Article
  • Title: p130Cas mediates the transforming properties of the anaplastic lymphoma kinase
  • Contributor: Ambrogio, Chiara; Voena, Claudia; Manazza, Andrea D.; Piva, Roberto; Riera, Ludovica; Barberis, Laura; Costa, Carlotta; Tarone, Guido; Defilippi, Paola; Hirsch, Emilio; Erba, Elisabetta Boeri; Mohammed, Shabaz; Jensen, Ole N.; Palestro, Giorgio; Inghirami, Giorgio; Chiarle, Roberto
  • Published: American Society of Hematology, 2005
  • Published in: Blood, 106 (2005) 12, Seite 3907-3916
  • Language: English
  • DOI: 10.1182/blood-2005-03-1204
  • ISSN: 0006-4971; 1528-0020
  • Origination:
  • Footnote:
  • Description: <jats:p>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.</jats:p>
  • Access State: Open Access