The cancer antigen CA125 represents a novel counter receptor for galectin-1

Abstract

CA125 is an ovarian cancer antigen whose recently elucidated primary structure suggests that CA125 is a giant mucin-like glycoprotein present on the cell surface of tumor cells. Here, we establish a functional link between CA125 and β-galactoside-binding, cell-surface lectins, which are components of the extracellular matrix implicated in the regulation of cell adhesion, apoptosis, cell proliferation and tumor progression. On the basis of mass spectrometry and immunological analyses, we find that CA125 is a counter receptor for galectin-1, as both soluble and membrane-associated fragments of CA125 derived from HeLa cell lysates are shown to bind specifically to human galectin-1 with high efficiency. This interaction is demonstrated (1) to depend on β-galactose-terminated, O-linked oligosaccharide chains of CA125, (2) to be preferential for galectin-1 versus galectin-3 and (3) to be regulated by the cellular background in which CA125 is expressed. Despite lacking a conventional signal peptide, a CA125 C-terminal fragment of 1148 amino acids, representing less than 10% of the full-length protein, retains the ability to integrate into secretory membranes such as the endoplasmic reticulum (ER) and the Golgi, and is targeted to the plasma membrane by conventional secretory transport. As demonstrated by a novel assay that reconstitutes non-conventional secretion of galectin-1 based on fluorescence-activated cell sorting (FACS), we find that tumor-derived HeLa cells expressing endogenous CA125 present more than ten times as much galectin-1 on their surface compared with non-tumor-derived, CA125-deficient CHO cells. Intriguingly, both the galectin-1 expression level and the cell-surface binding capacity for galectin-1 are shown to be similar in CHO and HeLa cells, suggesting that CA125 might be a factor involved in the regulation of galectin-1 export to the cell surface.

Implantation mechanisms: insights from the sheep

“…In addition to a conserved CRD, galectin-15 also contains predicted cell attachment sequences (LDV and RGD) that could mediate binding to integrins in ECM proteins (Kimber & Spanswick 2000, Wang & Armant 2002. Other galectins bind integrins as well as fibronectin, laminin and MUC16/CA-125, because these proteins are modified with b-galactoside sugars (Cooper 2002, Seelenmeyer et al 2003, Yang & Liu 2003. Functional studies of other galectins have implicated these proteins in cell growth, differentiation and apoptosis as well as in cell adhesion, chemoattraction and migration (Barondes et al 1994, Hughes 2001, Yang & Liu 2003.…”

Cell-surface heparan sulfate proteoglycans are essential components of the unconventional export machinery of FGF-2

“…These include the proangiogenic lectins FGF-1 and FGF-2 (13)(14)(15)(16)(17)(18)(19)(20)(21), the inflammatory cytokines interleukin 1␤ (22)(23)(24) and macrophage migration inhibitory factor (MIF) (25), and galectins, which are ␤-galactoside-specific lectins of the extracellular matrix that function in development and immune regulation (26)(27)(28)(29)(30)(31)(32)(33)(34). Consistent with their critical functions, unconventional secretory processes are, in most cases, specifically regulated (reviewed in refs.…”

CA-125 of fetal origin can act as a ligand for dendritic cell-specific ICAM-3-grabbing non-integrin

“…Distinct types of human lectin with different specificities and binding requirements were demonstrated to recognize CA-125. The siglecs (sialic-acid Ig-like lectins), which are a subgroup of I-type lectins, and the galectins (beta-galactoside-binding lectins) were found to interact with MUC16 [9][10][11][12]. Specifically, siglec-9 was identified as a ligand for MUC16 on human NK cells, B cells, and monocytes [11].…”

“…Specifically, siglec-9 was identified as a ligand for MUC16 on human NK cells, B cells, and monocytes [11]. Galectin-1 (gal-1) and galectin-3 (gal-3) were shown to be receptors for MUC16 on membrane-associated fragments of HeLa cell lysates and on the ocular epithelial cell surface [9,10]. In addition, MUC16 expressed by metastatic pancreatic cancer cells was identified as a ligand for E-and L-selectin [13].…”