Syk-dependent tyrosine phosphorylation of 3BP2 is required for optimal FcRγ-mediated phagocytosis and chemokine expression in U937 cells

Abstract

The adaptor protein c-Abl SH3 domain binding protein-2 (3BP2) is tyrosine phosphorylated by Syk in response to cross-linking of antigen receptors, which in turn activates various immune responses. Recently, a study using the mouse model of cherubism, a dominant inherited disorder caused by mutations in the gene encoding 3BP2, showed that 3BP2 is involved in the regulation of phagocytosis mediated by Fc receptor for IgG (FcγR) in macrophages. However, the molecular mechanisms underlying 3BP2-mediated regulation of phagocytosis and the physiological relevance of 3BP2 tyrosine phosphorylation remains elusive. In this study, we established various gene knockout U937 cell lines using the CRISPR/Cas9 system and found that 3BP2 is rapidly tyrosine phosphorylated by Syk in response to cross-linking of FcγRI. Depletion of 3BP2 caused significant reduction in the Fc receptor γ chain (FcRγ)-mediated phagocytosis in addition to the FcγRI-mediated induction of chemokine mRNA for IL-8, CCL3L3 and CCL4L2. Syk-dependent tyrosine phosphorylation of 3BP2 was required for overcoming these defects. Finally, we found that the PH and SH2 domains play important roles on FcγRI-mediated tyrosine phosphorylation of 3BP2 in HL-60 cells. Taken together, these results indicate that Syk-dependent tyrosine phosphorylation of 3BP2 is required for optimal FcRγ-mediated phagocytosis and chemokine expression.

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

“…SH3BP2 interacts with several proteins including spleen tyrosine kinase (SYK), 14-3-3, VAV, LYN, SHP-1, and PLCγ1/2, indicating that SH3BP2 is involved in a variety of cellular functions. (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) Gainof-function mutations in SH3BP2 are responsible for a human craniofacial disorder, cherubism (OMIM#118400). (32) Analysis of a knock-in mouse model for cherubism revealed that a cherubism mutation increases osteoclastogenesis induced by RANKL and TNF-α and enhances macrophage responsiveness to pathogen-associated molecular patterns (PAMPs) via TLRs.…”

Tankyrase (PARP5) Inhibition Induces Bone Loss through Accumulation of Its Substrate SH3BP2

“…As described in the previous section, SH3BP2 is ubiquitously expressed in various immune cells, such as macrophages and lymphocytes. Previous studies revealed that excessive amounts of SH3BP2 in macrophages enhance the production of inflammatory cytokines [52,65,68] and increase phagocytic activities [88,89]. Additionally, a deficiency in SH3BP2 impairs B-cell functions [90,91].…”

A Paradigm Shift in the Management of Cherubism? A Preliminary Report Using Imatinib

“…6,7 Although the full extent of this protein's actions are still being discovered, mouse models have shown that this protein attaches to the tyrosine kinase c-abl, leading to an upregulation of inflammation and osteoclastogenesis. [8][9][10] Imatinib is an active inhibitor of the c-abl, c-kit, and platelet-derived growth factor tyrosine kinases. 4 Inhibiting c-abl could directly mitigate the effects of the aberrant 3BP2 protein.…”