Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity
| Autor: | Stephan W. Morris, Serge Roche, Catherine Greenland, Bernard Payrastre, Georges Delsol, Ren Yuan Bai, Justus Duyster, Daniel Cussac, Michèle Allouche |
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| Rok vydání: | 2003 |
| Předmět: |
Proto-Oncogene Proteins pp60(c-src)
Immunology Biology Biochemistry Translocation Genetic Jurkat Cells hemic and lymphatic diseases medicine Animals Humans Anaplastic lymphoma kinase Anaplastic Lymphoma Kinase Phosphorylation Kinase activity Tyrosine Nucleoplasmins Anaplastic large-cell lymphoma Nucleophosmin integumentary system Nuclear Proteins Receptor Protein-Tyrosine Kinases Blood Proteins Cell Biology Hematology Protein-Tyrosine Kinases Phosphoproteins medicine.disease Fusion protein Chromosomes Human Pair 2 Cancer research Chromosomes Human Pair 5 Lymphoma Large B-Cell Diffuse Signal transduction Tyrosine kinase Cell Division |
| Zdroj: | Blood. 103:1464-1471 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2003-04-1038 |
| Popis: | Anaplastic large-cell lymphomas (ALCLs) are lymphomas of T or null phenotype often associated with a chromosomal translocation, t(2;5)(p23;q35). This translocation leads to the expression of a hybrid protein consisting of the N-terminal portion of nucleophosmin (NPM) and the intracellular domain of the anaplastic lymphoma kinase (ALK). NPM-ALK possesses a constitutive tyrosine kinase activity responsible for its oncogenic property through activation of downstream effectors such as phospholipase C gamma (PLC-gamma) and the type IA phosphoinositide 3-kinase. Here, we show that the Src-kinases, particularly pp60(c-src), associate with and are activated by NPM-ALK expression in various cells, and in cell lines established from patients with ALCL. The kinase activity and the tyrosine 418 of NPM-ALK are required for its association with Src-kinases. Y418F mutation of NPM-ALK impaired its association with Src-kinases and strongly reduced the proliferation rate of Ba/F3 cells. In agreement, Src-kinase inhibitors or pp60(c-src) siRNA significantly decreased the proliferation rate of NPM-ALK-positive ALCL cell lines. Moreover, using active or inactive forms of pp60(c-src) and NPM-ALK, we provide evidence that NPM-ALK is a potential substrate of pp60(c-src). Overall, our data place Src-kinases as new important downstream effectors of NPM-ALK and as attractive potential therapeutic targets for new ALCL treatment. |
| Databáze: | OpenAIRE |
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