Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity

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作者：

D Cussac，C Greenland，S Roche，RY Bai，B Payrastre

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摘要：

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 Cγ (PLC-γ) and the type IA phosphoinositide 3-kinase. Here, we show that the Src-kinases, particularly pp60c-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 pp60c-src siRNA significantly decreased the proliferation rate of NPM-ALK–positive ALCL cell lines. Moreover, using active or inactive forms of pp60c-src and NPM-ALK, we provide evidence that NPM-ALK is a potential substrate of pp60c-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.

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关键词：

Animals Humans Jurkat Cells Chromosomes, Human, Pair 2 Chromosomes, Human, Pair 5 Tyrosine Blood Proteins Phosphoproteins Nuclear Proteins Phosphorylation