en
Scientific article
English

Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts

Published inBlood, vol. 111, no. 4, p. 2310-2320
Publication date2008
Abstract

B-non-Hodgkin lymphomas (B-NHLs) use a raft-associated signalosome made of the constitutively active Lyn kinase, the tyrosine phosphorylated Cbp/PAG adaptor, and tyrosine phosphorylated STAT3 transcription factor. No such "signalosome" is found in rafts of ALK(+) T lymphoma and Hodgkin-derived cell lines, despite similar Cbp/PAG, Lyn, and STAT3 expression and similar amounts of raft sphingolipids. Stable association of the signalosome with B-NHL rafts requires (1) a Lyn kinase (auto)phosphorylated in its regulatory and active site tyrosines, (2) a Cbp/PAG adaptor phosphorylated at tyrosine 317 and bound to Lyn SH2 via phosphotyrosine 299 and neighboring residues, and (3) a tyrosine phosphorylated STAT3 linked via SH2 to the regulatory, C-terminal tyrosine of Lyn. No Csk appears to be part of this B-NHL signalosome. An oncogenic role for Lyn was shown after exposure of B-NHL lines to Lyn inhibitors that prevented Lyn and Cbp/PAG phosphorylation, dissociated the signalosome from rafts, and eventually induced death. Cell death followed decreases in Lyn or Cbp/PAG expression levels in one mantle cell lymphoma line, but not in a Hodgkin-derived one. The Lyn-Cbp/PAG signalosome appears to control proliferation and survival in most B-NHLs and constitutes a therapeutic target in B-NHL cells that exhibit oncogenic "addiction" to the Lyn kinase.

Keywords
  • Adaptor Proteins Signal Transducing/genetics/metabolism
  • Carrier Proteins/metabolism
  • Cell Death/drug effects
  • Cell Division
  • Cell Line Tumor
  • Cell Survival
  • Corticosterone
  • Gene Silencing
  • Humans
  • Lymphoma B-Cell/enzymology/pathology
  • Membrane Microdomains/enzymology/metabolism
  • Membrane Proteins/genetics/metabolism
  • Pyrimidines/toxicity
  • Pyrroles/toxicity
  • RNA Small Interfering/genetics
  • STAT3 Transcription Factor/genetics/metabolism
  • Src-Family Kinases/genetics/metabolism
Citation (ISO format)
TAUZIN, Sébastien et al. Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts. In: Blood, 2008, vol. 111, n° 4, p. 2310–2320. doi: 10.1182/blood-2007-05-090985
Main files (1)
Article (Accepted version)
accessLevelRestricted
Identifiers
ISSN of the journal0006-4971
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