Lyn, a member of the Src family of kinases, is a key factor in the dys-regulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn's action is spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and serine/threonine phosphatase 2A, eventually triggering apoptosis. Furthermore, the activation of PP2A by using MP07-66, a novel FTY720 analog, stimulated SHP-1 activity via dephosphorylation of phospho-S591, which unveiled the existence of a positive feedback signaling loop involving the two phosphatases. In addition to providing further insights into the molecular basis of this disease, our findings indicate that the PP2A/SHP-1 axis may emerge as an attractive, novel target for the development of alternative strategies in the treatment of chronic lymphocytic leukemia.

Targeted activation of the SHP-1/PP2A signaling axis elicits apoptosis of chronic lymphocytic leukemia cells

Tibaldi, Elena
Membro del Collaboration Group
;
Pagano, Mario Angelo
Membro del Collaboration Group
;
Frezzato, Federica
Membro del Collaboration Group
;
Trimarco, Valentina
Membro del Collaboration Group
;
Facco, Monica
Membro del Collaboration Group
;
Zagotto, Giuseppe
Membro del Collaboration Group
;
Ribaudo, Giovanni
Membro del Collaboration Group
;
Pavan, Valeria
Membro del Collaboration Group
;
Bordin, Luciana
Membro del Collaboration Group
;
Visentin, Andrea
Membro del Collaboration Group
;
Zonta, Francesca
Membro del Collaboration Group
;
Semenzato, Gianpietro
Membro del Collaboration Group
;
Brunati, Anna Maria
Membro del Collaboration Group
;
Trentin, Livio
Membro del Collaboration Group
2017

Abstract

Lyn, a member of the Src family of kinases, is a key factor in the dys-regulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn's action is spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and serine/threonine phosphatase 2A, eventually triggering apoptosis. Furthermore, the activation of PP2A by using MP07-66, a novel FTY720 analog, stimulated SHP-1 activity via dephosphorylation of phospho-S591, which unveiled the existence of a positive feedback signaling loop involving the two phosphatases. In addition to providing further insights into the molecular basis of this disease, our findings indicate that the PP2A/SHP-1 axis may emerge as an attractive, novel target for the development of alternative strategies in the treatment of chronic lymphocytic leukemia.
2017
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/3245012
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