Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts.
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.
Tauzin
Sebastien
S
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Ding
Heidrun
H
Khatib
Karim
K
Ahmad
Ishtiaq
I
Burdevet
Dimitri
D
van Echten-Deckert
Gerhild
G
Lindquist
Jonathan A
JA
Schraven
Burkhart
B
Din
Nasir-Ud-
NU
Borisch
Bettina
B
Hoessli
Daniel C
DC
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D003345:Corticosterone; D020868:Gene Silencing; D006801:Humans; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000473:pathology; D021962:Membrane Microdomains / Q000201:enzymology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000633:toxicity; D011758:Pyrroles / Q000633:toxicity; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C472714:CGP 76030; D002352:Carrier Proteins; D008565:Membrane Proteins; C498710:PAG1 protein, human; D011743:Pyrimidines; D011758:Pyrroles; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D003345:Corticosterone