51. p66Shc deficiency enhances CXCR4 and CCR7 recycling in CLL B cells by facilitating their dephosphorylation-dependent release from β-arrestin at early endosomes.
- Author
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Patrussi L, Capitani N, Cattaneo F, Manganaro N, Gamberucci A, Frezzato F, Martini V, Visentin A, Pelicci PG, D'Elios MM, Trentin L, Semenzato G, and Baldari CT
- Subjects
- Adenine analogs & derivatives, Adult, Animals, Case-Control Studies, Cells, Cultured, Endosomes drug effects, Endosomes pathology, Germ-Line Mutation, Humans, Mice, Mice, Knockout, Phosphorylation genetics, Piperidines, Proteolysis, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Endosomes metabolism, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Receptors, CCR7 metabolism, Receptors, CXCR4 metabolism, Src Homology 2 Domain-Containing, Transforming Protein 1 genetics, beta-Arrestins metabolism
- Abstract
Neoplastic cell traffic abnormalities are central to the pathogenesis of chronic lymphocytic leukemia (CLL). Enhanced CXC chemokine receptor-4 (CXCR4) and chemokine receptor-7 (CCR7) recycling contributes to the elevated surface levels of these receptors on CLL cells. Here we have addressed the role of p66Shc, a member of the Shc family of protein adaptors the expression of which is defective in CLL cells, in CXCR4/CCR7 recycling. p66Shc reconstitution in CLL cells reduced CXCR4/CCR7 recycling, lowering their surface levels and attenuating B-cell chemotaxis, due to their accumulation in Rab5
+ endosomes as serine-phosphoproteins bound to β-arrestin. This results from the ability of p66Shc to inhibit Ca2+ and PP2B-dependent CXCR4/CCR7 dephosphorylation and β-arrestin release. We also show that ibrutinib, a Btk inhibitor that promotes leukemic cell mobilization from lymphoid organs, reverses the CXCR4/CCR7 recycling abnormalities in CLL cells by increasing p66Shc expression. These results, identifying p66Shc as a regulator of CXCR4/CCR7 recycling in B cells, underscore the relevance of its deficiency to CLL pathogenesis and provide new clues to the mechanisms underlying the therapeutic effects of ibrutinib.- Published
- 2018
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