Basigin-2 Is a Cell Surface Receptor for Soluble Basigin Ligand

Abstract

The metastatic spread of a tumor is dependent upon the ability of the tumor to stimulate surrounding stromal cells to express enzymes required for tissue remodeling. The immunoglobulin superfamily protein basigin (EMMPRIN/CD147) is a cell surface glycoprotein expressed by tumor cells that stimulates matrix metalloproteinase and vascular endothelial growth factor expression in stromal cells. The ability of basigin to stimulate expression of molecules involved in tissue remodeling and angiogenesis makes basigin a potential target for the development of strategies to block metastasis. However, the identity of the cell surface receptor for basigin remains controversial. The goal of this study was to determine the identity of the receptor for basigin. Using a novel recombinant basigin protein (rBSG) corresponding to the extracellular domain of basigin, it was demonstrated that the native, nonglycosylated rBSG protein forms dimers in solution. Furthermore, rBSG binds to the surface of uterine fibroblasts, activates the ERK1/2 signaling pathway, and induces expression of matrix metalloproteinases 1, 2, and 3. Proteins that interact with rBSG were isolated using a biotin label transfer technique and sequenced by matrixassisted laser desorption ionization tandem mass spectrophotometry. The results demonstrate that rBSG interacts with basigin expressed on the surface of fibroblasts and is subsequently internalized. During internalization, rBSG associates with a novel form of human basigin (basigin-3). It was concluded that cell surface basigin functions as a membrane receptor for soluble basigin and this homophilic interaction is not dependent upon glycosylation of the basigin ligand.The metastatic spread of cancer cells within host tissue is dependent upon the local microenvironment surrounding the primary tumor. Within this microenvironment, cancer cells stimulate surrounding stromal cells to express factors required for remodeling of the host tissue, thus allowing for the survival, proliferation, and metastasis of the tumor (1). Therefore, an understanding of the molecules mediating tumor-stromal cell interactions is critical for the development of strategies needed to diagnose and treat metastatic cancers. This need is underscored by the fact that many molecules identified as biological markers for metastatic cells are also expressed by host cells under normal physiological conditions (2). One particularly good example of such a molecule is the cell surface glycoprotein basigin. Basigin is an integral membrane glycoprotein belonging to the immunoglobulin superfamily, and it is expressed on numerous cell types (reviewed in Refs. 2-4). Originally identified in LX-1 lung carcinoma cells as a secreted factor capable of stimulating the collagenase activity of human fibroblasts, basigin has been identified independently in several different model systems resulting in a long list of acronyms for this molecule including tumor collagenase stimulatory factor (5-7), EMMPRIN (8), neurothelin (9), OX-47 (10), gp42 (11), CE9 (12), ...

Regulation of invadopodia formation and activity by CD147

“…5C). The results of some previous studies suggest strongly that high levels of glycosylation are necessary for induction of MMP production (Guo et al, 1997;Tang and Hemler, 2004), whereas others have demonstrated robust MMP production after treatment with nonglycosylated CD147 (Belton et al, 2008) or CD147 substituted only with the disaccharide, chitobiose (Kawakami et al, 2011). Clearly, further investigation is required to elucidate the role of glycosylation in CD147 activities in different contexts.…”

Up‐regulated basigin‐2 in microglia induced by hypoxia promotes retinal angiogenesis

“…Basigin‐2 (NM_198589) is a major isoform of basigin, and it is ubiquitously expressed. While basigin‐1 transcript (NM_001728), with a third immunoglobulin domain (Ig0), is only expressed specifically in the retinal photoreceptors 19, 26, 27. Basigin‐1, associating with a protein secreted from rods, being named as rod‐derived cone viability factor (RdCVF) and glucose transporter (Glut)‐1, form a complex at the cone surface to increase glucose uptake and promotes cone survival 28, 29.…”

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

“…CD147 was initially identified as an inducer of the expression of MMPs, including MMP-1, -2, -3, -9, and -11, in co-cultured tumor cells and fibroblasts. Several studies have shown that soluble CD147 is capable of inducing MMP production in fibroblasts expressing CD147, as well as in tumor cells (Belton et al, 2008). The fact that CD147 is overexpressed in a number of carcinoma tissues, coupled with its ability to stimulate MMP secretion, suggests that it serves as a key regulator of oncogenesis (Iacono et al, 2007).…”