The sphingolipid-rich rafts of ALK+ lymphomas downregulate the Lyn-Cbp/PAG signalosome.
Human anaplastic lymphoma kinase (ALK) + lymphomas express the constitutively active ALK as a fusion protein that drives several survival pathways. The catalytic domain of the anaplastic receptor tyrosine kinase is frequently fused with the nuclear localization protein nucleophosmin but may also fuse with other proteins that associate it with other subcellular structures. Similarly to other B human lymphomas, ALK+ lymphomas express the Cbp/PAG adaptor protein and the non-receptor Lyn kinase in the plasma membrane. In the majority of human lymphomas, the Cbp/PAG adaptor and the Lyn kinase constitute an oncogenic signalosome that serves as a membrane anchor for other signaling enzymes and transcription factors. We show that ALK+ lymphoma membranes harbor sphingolipid-rich microdomains (rafts) in which Lyn is poorly active. However, Lyn activity and consequently Cbp/PAG tyrosine phosphorylation can be restored by extracting sphingolipids from ALK+ lymphoma plasma membranes. In the membrane environment of ALK+ lymphoma rafts, where the glycosphingolipid to signaling protein ratio is higher than in B-NHL rafts, the Lyn activity is suboptimal and does not allow the formation of an efficient Lyn-Cbp/PAG signalosome.
Yerly
Stéphane
S
Department of Pathology and Immunology, Faculty of Medicine, Centre Médical Universitaire, rue Michel-Servet, Geneva, Switzerland.
Ding
Heidrun
H
Tauzin
Sébastien
S
van Echten-Deckert
Gerhild
G
Borisch
Bettina
B
Hoessli
Daniel C
DC
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000077548:Anaplastic Lymphoma Kinase; D002462:Cell Membrane; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000378:metabolism*; D021962:Membrane Microdomains / Q000737:chemistry / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D015398:Signal Transduction / Q000502:physiology*; D013107:Sphingolipids / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C498710:PAG1 protein, human; D013107:Sphingolipids; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases