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1.
Biochem Biophys Res Commun ; 372(2): 351-5, 2008 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-18501703

RESUMO

Phosphatidylinositol 5-monophosphate (PtdIns5P), one of the latest phosphoinositides discovered, has been suggested to play important cellular functions. Here, we report the presence of higher levels of this lipid in cells expressing the oncogenic tyrosine kinase nucleophosmin anaplastic lymphoma kinase (NPM-ALK), a chimeric protein found in the large majority of anaplastic large cell lymphomas (ALCLs). In addition, we describe that a pool of PtdIns5P is located in the membrane extensions characteristic of NPM-ALK-transformed cells. Finally, we show that the increase of PtdIns5P is controlled by the kinase PIKfyve, which is known for its role in vesicular trafficking. These data suggest for the first time a role of PtdIns5P and PIKfyve in oncogenesis, potentially linking intracellular trafficking to cancer.


Assuntos
Transformação Celular Neoplásica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Transformação Celular Neoplásica/genética , Humanos , Camundongos , Células NIH 3T3 , Fosfatos de Fosfatidilinositol/análise , Proteínas Tirosina Quinases/genética
2.
Oncogene ; 27(19): 2728-36, 2008 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-17998938

RESUMO

The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60(c-src), Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Linfoma Anaplásico de Células Grandes/enzimologia , Proteínas Tirosina Quinases/metabolismo , Proteínas Tirosina Quinases/fisiologia , Proteínas Proto-Oncogênicas c-vav/metabolismo , Transdução de Sinais/fisiologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Quinase do Linfoma Anaplásico , Animais , Proteína Tirosina Quinase CSK , Linhagem Celular Tumoral , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Humanos , Camundongos , Células NIH 3T3 , Proteínas Nucleares/fisiologia , Nucleofosmina , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-vav/fisiologia , Receptores Proteína Tirosina Quinases , Quinases da Família src/fisiologia
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