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PMID: 16105984 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

p130Cas mediates the transforming properties of the anaplastic lymphoma kinase.

Blood ·Vol. 106 ·No. 12 ·2005-12-01 ·Pages 3907-16

Ambrogio C, Voena C, Manazza AD, Piva R, Riera L, Barberis L, Costa C, Tarone G, Defilippi P, Hirsch E, Boeri Erba E, Mohammed S, Jensen ON, Palestro G, Inghirami G, Chiarle R

Abstract

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-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 wild-type cells, indicating an essential role of p130Cas activation in ALK-mediated transformation.

MeSH Terms
Anaplastic Lymphoma Kinase Animals Cell Line Cell Movement/physiology Cell Transformation, Neoplastic/metabolism Crk-Associated Substrate Protein/metabolism Cytoskeleton/metabolism Electrophoresis, Polyacrylamide Gel Humans Immunoblotting Immunoprecipitation Lymphoma, Large B-Cell, Diffuse/metabolism Mass Spectrometry Mice Oncogene Proteins, Fusion/metabolism Phosphorylation Protein-Tyrosine Kinases/metabolism Receptor Protein-Tyrosine Kinases Tumor Cells, Cultured
Chemicals
Crk-Associated Substrate Protein Oncogene Proteins, Fusion ALK protein, human Alk protein, mouse Anaplastic Lymphoma Kinase Protein-Tyrosine Kinases Receptor Protein-Tyrosine Kinases
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Ambrogio Chiara
Center for Experimental Research and Medical Studies and Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy.
Voena Claudia
Manazza Andrea D
Piva Roberto
Riera Ludovica
Barberis Laura
Costa Carlotta
Tarone Guido
Defilippi Paola
Hirsch Emilio
Boeri Erba Elisabetta
Mohammed Shabaz
Jensen Ole N
Palestro Giorgio
Inghirami Giorgio
Chiarle Roberto
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2005-03-1204
Published
2005-12-01
Epub
2005-00-16
Pages
3907-16
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895100
Subset
IM
Grants
NCI NIH HHS · R01-CA64033 · United States
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1182/blood-2005-03-1204 PMC Full Text View journal details
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