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

Ding, Heidrun
Ahmad, Ishtiaq
van Echten-Deckert, Gerhild
Lindquist, Jonathan A.
Schraven, Burkhart
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Published in Blood. 2008, vol. 111, no. 4, p. 2310-20
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/metabolismCarrier Proteins/metabolismCell Death/drug effectsCell DivisionCell Line TumorCell SurvivalCorticosteroneGene SilencingHumansLymphoma B-Cell/enzymology/pathologyMembrane Microdomains/enzymology/metabolismMembrane Proteins/genetics/metabolismPyrimidines/toxicityPyrroles/toxicityRNA Small Interfering/geneticsSTAT3 Transcription Factor/genetics/metabolismSrc-Family Kinases/genetics/metabolism
PMID: 18070987
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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. 2310-20. doi: 10.1182/blood-2007-05-090985 https://archive-ouverte.unige.ch/unige:678

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Deposited on : 2009-02-06

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