p66Shc deficiency enhances CXCR4 and CCR7 recycling in CLL B cells by facilitating their dephosphorylation-dependent release from β-arrestin at early endosomes

p66Shc deficiency enhances CXCR4 and CCR7 recycling in CLL B cells by facilitating their... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oncogene Springer Journals

p66Shc deficiency enhances CXCR4 and CCR7 recycling in CLL B cells by facilitating their dephosphorylation-dependent release from β-arrestin at early endosomes

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Publisher
Nature Publishing Group UK
Copyright
Copyright © 2018 by Macmillan Publishers Limited, part of Springer Nature
Subject
Medicine & Public Health; Medicine/Public Health, general; Internal Medicine; Cell Biology; Human Genetics; Oncology; Apoptosis
ISSN
0950-9232
eISSN
1476-5594
D.O.I.
10.1038/s41388-017-0066-2
Publisher site
See Article on Publisher Site

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.

Journal

OncogeneSpringer Journals

Published: Jan 12, 2018

References

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