Protein with the Lyn Tyrosine Kinase in Human B-nhl Rafts

To control proliferation and apoptosis, B-non-Hodgkin lymphomas utilize a plasma membrane, 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. We suggest that stable association of the signalosome with B-NHL rafts requires (i) a Lyn kinase (auto)phosphorylated in its regulatory and active site tyrosines, (ii) a Cbp/PAG adaptor phosphorylated at tyrosine 317 and bound to Lyn SH2 via phosphotyrosine 299 and neighboring residues and (iii) a tyrosine phosphorylated STAT3 linked via SH2 to the regulatory, C-terminal tyrosine of Lyn. The cytoplasmic Csk kinase that negatively controls the Src kinase activity in human T lymphocytes is not involved in the B-NHL signalosome, strongly suggesting that associated Lyn and Cbp/PAG form a constitutively active signalosome in B-NHLs. An oncogenic role for Lyn was shown following exposure of B-NHL lines to small molecular weight Lyn inhibitors that prevented Lyn and Cbp/PAG phosphorylation, dissociated the signalosome from rafts and eventually induced apoptosis. Apoptotic cell death also followed decreases in Lyn or Cbp/PAG expression levels in one mantle-cell lymphoma line, but not in a Hodgkin-derived one, supporting the notion that B-NHLs are oncogenically ‘‘addicted’’ to the Lyn/PAG signalosome. The Lyn-Cbp/PAG signalosome therefore exert a proximal control on proliferation and survival in most B-NHLs, and represent a suitable therapeutic target in B-NHL cells that exhibit oncogenic ‘‘addiction’’ to the Lyn kinase.