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

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.

• Authors: Sebastien Tauzin, Heidrun Ding, Karim Khatib, Ishtiaq Ahmad, Dimitri Burdevet, Gerhild van Echten-Deckert, Jonathan A Lindquist, Burkhart Schraven, Nasir-Ud- Din, Bettina Borisch, Daniel C Hoessli
• Journal: Blood (Blood) Vol. 111 Issue 4 Pg. 2310-20 (Feb 15 2008) ISSN: 0006-4971 [Print] United States
• PMID: 18070987 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• CGP 76030
• Carrier Proteins
• Membrane Proteins
• PAG1 protein, human
• Pyrimidines
• Pyrroles
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human
• lyn protein-tyrosine kinase
• src-Family Kinases
• Corticosterone

Topics

• 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)