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

Article Article scientifique Article Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts eng 2008 author Tauzin Sébastien 135564 author Ding Heidrun author Khatib Karim 108201 author Ahmad Ishtiaq author Burdevet Dimitri 126297 author van Echten-Deckert Gerhild author Lindquist Jonathan A. author Schraven Burkhart author Din Nasir-ud- author Borisch Bettina 104254 author Hoessli Daniel 25326 2310-2320 10.1182/blood-2007-05-090985 18070987 0006-4971 http://bloodjournal.hematologylibrary.org/cgi/content/full/111/4/2310 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. 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 Dewey 613 Dewey 616.07 Dewey 617 137 Département de pathologie et immunologie 21F 57 Département de chirurgie 222 66 Institut de santé globale 22A1 false Blood 111 4 367d8594-ea47-48f6-8b3d-11d764f6e68b Article (Accepted version) Restricted 18070987.pdf 1812925 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de chirurgie Faculté de médecine / Section de médecine clinique / Département de santé et médecine communautaires / Institut de santé globale

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Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts	Blood			2008	702	0

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Burdevet, Dimitri