Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A.
Aberrant protein kinase activities, and the consequent dramatic increase of Ser/Thr and -Tyr phosphorylation, promote the deregulation of the survival pathways in chronic lymphocytic leukemia (CLL), which is crucial to the pathogenesis and progression of the disease. In this study, we show that the tumor suppressor protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases, is in an inhibited form because of the synergistic contribution of 2 events, the interaction with its physiologic inhibitor SET and the phosphorylation of Y307 of the catalytic subunit of PP2A. The latter event is mediated by Lyn, a Src family kinase previously found to be overexpressed, delocalized, and constitutively active in CLL cells. This Lyn/PP2A axis accounts for the persistent high level of phosphorylation of the phosphatase's targets and represents a key connection linking phosphotyrosine- and phosphoserine/threonine-mediated oncogenic signals. The data herein presented show that the disruption of the SET/PP2A complex by a novel FTY720-analog (MP07-66) devoid of immunosuppressive effects leads to the reactivation of PP2A, which in turn triggers apoptosis of CLL cells. When used in combination with SFK inhibitors, the action of MP07-66 is synergistically amplified, providing a new option in the therapeutic strategy for CLL patients.
Department of Molecular Medicine.
Francesca
F
Zonta
Department of Pharmaceutical and Pharmacological Sciences, and.
Mario Angelo
MA
Pagano
Department of Medicine, University of Padua, Padua, Italy; and Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica, Padua, Italy.
Livio
L
Trentin
Department of Molecular Medicine.
Elena
E
Tibaldi
Department of Medicine, University of Padua, Padua, Italy; and Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica, Padua, Italy.
Federica
F
Frezzato
Department of Medicine, University of Padua, Padua, Italy; and Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica, Padua, Italy.
Valentina
V
Trimarco
Department of Medicine, University of Padua, Padua, Italy; and Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica, Padua, Italy.
Monica
M
Facco
Department of Pharmaceutical and Pharmacological Sciences, and.
Giuseppe
G
Zagotto
Department of Pharmaceutical and Pharmacological Sciences, and.
Valeria
V
Pavan
Department of Pharmaceutical and Pharmacological Sciences, and.
Giovanni
G
Ribaudo
Department of Molecular Medicine.
Luciana
L
Bordin
Department of Medicine, University of Padua, Padua, Italy; and Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica, Padua, Italy.
Gianpietro
G
Semenzato
Department of Molecular Medicine.
Anna Maria
AM
Brunati
D017209:Apoptosis / Q000187:drug effects; D004268:DNA-Binding Proteins; D000068876:Fingolimod Hydrochloride; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056488:Histone Chaperones / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011409:Propylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D060066:Protein Interaction Maps / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D056488:Histone Chaperones; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; C513473:SET protein, human; D014157:Transcription Factors; D019000:Phosphotyrosine; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine