Opposite Functions for Two Classes of Genes of the Human Carcinoembryonic Antigen Family

Abstract

The human carcinoembryonic antigen (CEA) family can be divided into two subgroups according to the means of anchorage of member glycoproteins to the cell membrane: glycophos-phatidyl inositol (GPI) linkage and transmembrane linkage. The GPI-linked members tend to be up-regulated in human tumours, whereas the transmembrane-linked members tend to be down-regulated. Thus the question as to whether the GPI members could be formally considered to function as onco-genes and the transmembrane members as tumour suppressors deserves consideration. Members of both subgroups function in vitro as intercellular adhesion molecules, but the characteristics of this adhesion, including temperature and divalent-cation dependence, differ markedly between the groups. Even the mechanism of intermolecular adhesion appears to differ fundamentally in that GPI-linked CEA-CEA binding involves a double reciprocal bonding between two domains, whereas transmembrane-linked biliary glycoprotein (BGP)-BGP binding requires only one domain. Finally, the ectopic expression of CEA in myoblasts can block myogenic differentiation leaving the cells with the ability to divide, while expression of BGP does not affect or may even accelerate myogenic differentiation. These differences in phenotypic effects in vitro thus mirror the differences observed in expression in tumours and support the view that the GPI and transmembrane groups have opposite effects on cells in relation to the malignant phenotype.

Homophilic adhesion of human CEACAM1 involves N-terminal domain interactions: structural analysis of the binding site

“…The avidity of adhesion was also reduced if the A2 domain was removed from the CEACAM1-4 soluble molecule. Whereas previous studies have shown that cells expressing CEACAM1-4L and -4S are able to mediate homophilic adhesion, 6,[64][65][66][67] our studies show that CEACAM1-4S in contrast to CEACAM1-4L transfectants bind less avidly to immobilized CEACAM1 molecules and suggest that the IgC2 and cytoplasmic domains of CEACAM1 may regulate the specificity and avidity of homophilic and heterophilic interactions or signaling functions. Several observations support this view.…”

Minimal mutations are required to effect a radical change in function in CEA family members of the Ig superfamily

“…Since only TM-anchored CEACAM1-like genes have been discovered in rodents, we and others have suggested a recent evolution of GPI-anchored CEA family members from a primordial TM-anchored gene (Hammarström et al, 1998;Stanners et al, 1995;Stanners et al, 1992;Zimmermann, 1998). In view of the rather dramatic changes in function implicated by the acquisition of the GPI anchor (see Introduction), we decided to examine the ease of derivation of GPI linkage from the TM domain of present-day human CEACAM1.…”

Difference in virus-binding activity of two distinct receptor proteins for mouse hepatitis virus

“…MHVR1 (mmCGM1) and MHVR2 (mmCGM2) have been reported to exhibit cell adhesion activity, though the properties of this activity are different between these two proteins; the adhesion activity of mmCGM1 works in a calcium-and temperature-dependent manner, while that of mmCGM2 is calcium-and temperature-independent (McCuaig eta]., 1992; Turbide eta]., 1992). The adhesion activity of mmCGM1 and mmCGM2 could be mediated by the N domain located at the N terminal region of the molecules as shown in human BGP (Stanners et al, 1995;Teixeira eta]., 1994). The same domain of the molecule interacts with the N-terminal region of the MHV S protein (Dveksler eta[., 1993 b;Kubo eta[., 1994).…”