p130Cas mediates the transforming properties of the anaplastic lymphoma kinase

被引:57
作者
Ambrogio, C
Voena, C
Manazza, AD
Piva, R
Riera, L
Barberis, L
Costa, C
Tarone, G
Defilippi, P
Hirsch, E
Erba, EB
Mohammed, S
Jensen, ON
Palestro, G
Inghirami, G
Chiarle, R
机构
[1] Univ Turin, Dept Biomed Sci & Human Oncol, I-10126 Turin, Italy
[2] Univ Turin, CERMS, I-10126 Turin, Italy
[3] Univ Turin, Dept Genet Biol & Biochem, I-10126 Turin, Italy
[4] Univ So Denmark, Dept Biochem & Mol Biol, Odense, Denmark
关键词
D O I
10.1182/blood-2005-03-1204
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 ALKpositive 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-ALK (K210R) 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 wildtype cells, indicating an essential role of p130Cas activation in ALK-mediated transformation.
引用
收藏
页码:3907 / 3916
页数:10
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