MFR, a Putative Receptor Mediating the Fusion of Macrophages

Abstract

We had previously identified a macrophage surface protein whose expression is highly induced, transient, and specific, as it is restricted to actively fusing macrophages in vitro and in vivo. This protein is recognized by monoclonal antibodies that block macrophage fusion. We have now purified this protein and cloned its corresponding cDNA. This protein belongs to the superfamily of immunoglobulins and is similar to immune antigen receptors such as the T-cell receptor, B-cell receptor, and viral receptors such as CD4. We have therefore named this protein macrophage fusion receptor (MFR). We show that the extracellular domain of MFR prevents fusion of macrophages in vitro and therefore propose that MFR belongs to the fusion machinery of macrophages. MFR is identical to SHPS-1 and BIT and is a homologue of P84, SIRP␣, and MyD-1, all of which have been recently cloned and implicated in cell signaling and cell-cell interaction events.Membrane fusion is a ubiquitous event that occurs in a wide range of cell biological processes. While intracellular membrane fusion mediating interorganelle traffic is well studied, much less is known about cell-cell fusion mediating sperm cell-oocyte, myoblast-myoblast, and macrophage-macrophage fusion. These fusion events are required for fertilization, muscle, and osteoclast development, respectively. In the case of mononuclear phagocytes, fusion is associated not only with the differentiation of osteoclasts, cells which play a key role in the pathogenesis of osteoporosis, but also with the formation of giant cells that are present in chronic inflammatory reactions and in tumors. Despite the biological and pathophysiological importance of intercellular fusion events, the actual molecular mechanisms of cell-cell fusion are still unclear.

SHPS-1 promotes the survival of circulating erythrocytes through inhibition of phagocytosis by splenic macrophages

“…[12][13][14] The spleen contains different types of macrophages, however, with each type residing in a specific region of the spleen and having a distinct function. 41,42 Most macrophages positive for the F4/80 antigen, which are thought to be responsible for phagocytosis and digestion of circulating RBCs, 5,6 are thus present in the red pulp area.…”

“…[1][2][3] Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), 7,8 also known as signal-regulatory protein ␣, 9 brain immunoglobulin (Ig)-like molecule with tyrosinebased activation motifs, 10 and p84 neural adhesion molecule, 11 is a transmembrane protein that is especially abundant in macrophages. [12][13][14] The putative extracellular region of SHPS-1 comprises 3 Ig-like domains, and its cytoplasmic region contains 4 tyrosine phosphorylation sites that mediate the binding of Src homology 2 domain-containing protein tyrosine phosphatases designated SHP-1 and SHP-2. 7,9 Tyrosine phosphorylation of SHPS-1 is regulated by various growth factors and cytokines as well as by integrinmediated cell adhesion to extracellular matrix proteins.…”

Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells

“…(13) Therefore, although the functions of osteoclasts and FBGCs differ, they express common molecules, such as DC-STAMP, that function in cell-cell fusion. (3) To date, various molecules have been identified that regulate fusion of osteoclasts or macrophages, including DC-STAMP, ATP6v0d2, CD47, CD44, CD9, CD81, MFR, E-cadherin, and meltrin-a (3,(14)(15)(16)(17)(18)(19)(20)(21) ATP6v0d2-deficient mice show significant reductions in fusion of either cell type. (21) DC-STAMP-deficient osteoclasts or FBGCs show a complete lack of cell-cell fusion, a function specific for macrophage lineage fusion, since fertilization and myotube formation is normal in DC-STAMP-deficient mice.…”

Src homology 2 domain‐containing protein tyrosine phosphatase substrate 1 regulates the induction of Langerhans cell maturation

“…One signal-regulatory protein, Src homology 2 domain-containing protein tyrosine phosphatase substrate 1 (SHPS-1) [19], is also known as signalregulatory protein a1 (SIRP a1) [20], BIT (brain Iglike molecule with tyrosine-based activation motifs) [21], P84 [22], MFR (macrophage fusion receptor) [23] and MyD-1 [24]. In mice, SHPS-1 is expressed in myeloid cells, including monocytes, macrophages and DC [25].…”