The 3BP2 Adapter Protein Is Required for Chemoattractant-Mediated Neutrophil Activation

Abstract

3BP2 is a pleckstrin homology and Src homology 2 domain-containing adapter protein mutated in cherubism, a rare autosomal-dominant human bone disorder. Previously, we have demonstrated a functional role for 3BP2 in peripheral B cell development and in peritoneal B1 and splenic marginal zone B cell-mediated Ab responses. In this study, we show that 3BP2 is required for G protein-coupled receptor-mediated neutrophil functions. Neutrophils derived from 3BP2-deficient (Sh3bp2−/−) mice failed to polarize their actin cytoskeleton or migrate in response to a gradient of chemotactic peptide, fMLF. Sh3bp2−/− neutrophils failed to adhere, crawl, and emigrate out of the vasculature in response to fMLF superfusion. 3BP2 is required for optimal activation of Src family kinases, small GTPase Rac2, neutrophil superoxide anion production, and for Listeria monocytogenes bacterial clearance in vivo. The functional defects observed in Sh3bp2−/− neutrophils may partially be explained by the failure to fully activate Vav1 guanine nucleotide exchange factor and properly localize P-Rex1 guanine nucleotide exchange factor at the leading edge of migrating cells. Our results reveal an obligate requirement for the adapter protein 3BP2 in G protein-coupled receptor-mediated neutrophil function.

SH3BP2 Gain-Of-Function Mutation Exacerbates Inflammation and Bone Loss in a Murine Collagen-Induced Arthritis Model

“…Therefore, we propose that a cumulative effect of these mechanisms is responsible for the increased osteoclast formation and subsequent bone loss in CII-immunized Sh3bp2 KI/+ mice. However, it should be noted that SH3BP2 is known to be involved in the diverse cell functions in various types of cells [13], [17], [19], [20], [54], [55], thereby we cannot exclude the possibility that other immune cells (e.g. NK cells, neutrophils, mast cells) as well as stromal cells (e.g.…”

“…SH3BP2 is expressed in various immune cells such as T cells, B cells, and macrophages as well as osteoclasts, indicating that SH3BP2 potentially regulates both immune and skeletal systems [13]–[17], [23]. Since inflammatory bone loss is mediated by complex interactions involving immune and bone cells [6]–[8], we investigated how SH3BP2 regulates the development of joint inflammation and bone destruction.…”

“…SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein, which is expressed primarily in immune cells including T cells, B cells, mast cells, neutrophils, and macrophages as well as osteoclasts [12]–[17]. SH3BP2 interacts with various proteins, including SYK [18], PLCγ [18], [19], SRC [20], [21], and VAV [22], and regulates intracellular signaling pathways in immune and skeletal systems [13]–[17], [23].…”

“…SH3BP2 interacts with various proteins, including SYK [18], PLCγ [18], [19], SRC [20], [21], and VAV [22], and regulates intracellular signaling pathways in immune and skeletal systems [13]–[17], [23]. Previously we have reported that gain-of-function mutations in SH3BP2 are responsible for cherubism (OMIM#118400) [24].…”

Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages

“…Conversely, phagocytic capacity of heterozygous cherubic BMM was exacerbated compared with that of WT macrophages ( Figure 2D). TLR and Fc receptors signal via different cytosolic molecular pathways (14,15), and 3BP2 has been implicated in a variety of membrane receptor signaling pathways, including those stimulated by immunoreceptors (4, 5), RANK (8), and GPCR (16). Therefore, it seems unlikely that 3BP2 interacts with specific regulators of either TLR or Fc receptor pathways in macrophages.…”