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

Tauzin, Sébastien; Ding, Heidrun; Khatib, Karim; Ahmad, Ishtiaq; Burdevet, Dimitri; van Echten-Deckert, Gerhild; Lindquist, Jonathan A.; Schraven, Burkhart; Din, Nasir-ud-; Borisch, Bettina; Hoessli, Daniel

doi:10.1182/blood-2007-05-090985

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Title		Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts
Authors		Tauzin, Sébastien Ding, Heidrun Khatib, Karim Ahmad, Ishtiaq Burdevet, Dimitri van Echten-Deckert, Gerhild Lindquist, Jonathan A. Schraven, Burkhart Din, Nasir-ud- Borisch, Bettina Hoessli, Daniel show all authors [1 - 11]
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/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
Identifiers		DOI: 10.1182/blood-2007-05-090985 PMID: 18070987
Full text		Article (Accepted version) (1.7 MB) - Limited access to UNIGE Other version: http://bloodjournal.hematologylibrary.org/cgi/content/full/111/4/2310
Structures		Faculté de médecine / Section de médecine clinique / Département de chirurgie Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de santé et médecine communautaires / Institut de santé globale
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. 2310-20. doi: 10.1182/blood-2007-05-090985 https://archive-ouverte.unige.ch/unige:678