Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas

A. Colomba, D. Courilleau, D. Ramel, D. D. Billadeau, E. Espinos, G. Delsol, B. Payrastre, F. Gaits-Iacovoni

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

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, pp60c-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.

Original languageEnglish (US)
Pages (from-to)2728-2736
Number of pages9
JournalOncogene
Volume27
Issue number19
DOIs
StatePublished - Apr 24 2008

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Keywords

  • Anaplastic large cell lymphomas
  • NPM-ALK
  • Rho GTPases
  • Vav3

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Colomba, A., Courilleau, D., Ramel, D., Billadeau, D. D., Espinos, E., Delsol, G., Payrastre, B., & Gaits-Iacovoni, F. (2008). Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas. Oncogene, 27(19), 2728-2736. https://doi.org/10.1038/sj.onc.1210921