RADICAL DIFFERENCES IN FUNCTIONS OF CLOSELY-RELATED MEMBERS OF THE HUMAN CARCINOEMBRYONIC ANTIGEN GENE FAMILY

The immunoglobulin superfamily represents an ancient, highly diversifi ed group of cell surface and extracellular molecules responsible for a wide range of molecular and cellular recognition functions. The human carcinoembryonic antigen (CEA) subfamily of the immunoglobulin superf amily presents evidence of continuing diversification of the immunoglo bulin family, in that some of its members, including CEA itself and no nspecific cross-reacting antigen (NCA), are expressed only in primates and not in rodents. These ''new'' members are glycophosphatidylinosit ol linked to the external cell membrane and are up-regulated in cancer , unlike members present in both rodents and primates, i.e., biliary g lycoprotein (BGP), which are transmembrane linked and down-regulated i n cancer. CEA, NCA, and BGP have all been shown to function in vitro a s intercellular adhesion molecules. We show here that the properties o f adhesion are radically different, in that BGP-mediated adhesion is r eversibly Ca2+ and Mg2+ dependent, temperature dependent, and ATP inhi bitable, whereas CEA- and NCA-mediated adhesion is the opposite in all aspects. Also, the novel double-reciprocal, antiparallel binding obse rved for CEA-CEA interactions is not seen for BGP. Finally, the myogen ic differentiation block demonstrated for the ectopic expression of CE A in myoblasts was also observed for NCA but not for BGP, which is con sistent with the changes in expression seen in cancer. The appearance of new CEA family members with such different properties is discussed in the context of evolution and cancer.