| First Author | Patrussi L | Year | 2018 |
| Journal | Oncogene | Volume | 37 |
| Issue | 11 | Pages | 1534-1550 |
| PubMed ID | 29326436 | Mgi Jnum | J:261034 |
| Mgi Id | MGI:6153461 | Doi | 10.1038/s41388-017-0066-2 |
| Citation | Patrussi L, et al. (2018) p66Shc deficiency enhances CXCR4 and CCR7 recycling in CLL B cells by facilitating their dephosphorylation-dependent release from beta-arrestin at early endosomes. Oncogene 37(11):1534-1550 |
| abstractText | 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 beta-arrestin. This results from the ability of p66Shc to inhibit Ca(2+) and PP2B-dependent CXCR4/CCR7 dephosphorylation and beta-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. |
