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

Oncogene. 2008 Apr 24;27(19):2728-36. doi: 10.1038/sj.onc.1210921. Epub 2007 Nov 12.

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, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • CSK Tyrosine-Protein Kinase
  • Cell Line, Tumor
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Guanine Nucleotide Exchange Factors / physiology
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / enzymology*
  • Mice
  • NIH 3T3 Cells
  • Nuclear Proteins / physiology
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein-Tyrosine Kinases / metabolism*
  • Protein-Tyrosine Kinases / physiology*
  • Proto-Oncogene Proteins c-vav / metabolism*
  • Proto-Oncogene Proteins c-vav / physiology
  • Receptor Protein-Tyrosine Kinases
  • Signal Transduction / physiology*
  • rac1 GTP-Binding Protein / metabolism*
  • src-Family Kinases / physiology

Substances

  • Guanine Nucleotide Exchange Factors
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-vav
  • VAV3 protein, human
  • Vav3 protein, mouse
  • nucleophosmin
  • p80(NPM-ALK) protein
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • rac1 GTP-Binding Protein