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, Daniel D Billadeau, E. Espinos, G. Delsol, B. Payrastre, F. Gaits-Iacovoni

Research output: Contribution to journalArticle

45 Citations (Scopus)

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

Fingerprint

Anaplastic Large-Cell Lymphoma
GTP Phosphohydrolases
Lymphocytes
NIH 3T3 Cells
src Homology Domains
src-Family Kinases
nucleophosmin
anaplastic lymphoma kinase
Cell Shape
Protein-Tyrosine Kinases
Small Interfering RNA
Cell Movement
Tyrosine
Fibroblasts
Biopsy
Costs and Cost Analysis
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas. / Colomba, A.; Courilleau, D.; Ramel, D.; Billadeau, Daniel D; Espinos, E.; Delsol, G.; Payrastre, B.; Gaits-Iacovoni, F.

In: Oncogene, Vol. 27, No. 19, 24.04.2008, p. 2728-2736.

Research output: Contribution to journalArticle

Colomba, A, Courilleau, D, Ramel, D, Billadeau, DD, 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, vol. 27, no. 19, pp. 2728-2736. https://doi.org/10.1038/sj.onc.1210921
Colomba, A. ; Courilleau, D. ; Ramel, D. ; Billadeau, Daniel D ; Espinos, E. ; Delsol, G. ; Payrastre, B. ; Gaits-Iacovoni, F. / Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas. In: Oncogene. 2008 ; Vol. 27, No. 19. pp. 2728-2736.
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