Evolution of a Tumorigenic Property Conferred by Glycophosphatidyl-Inositol Membrane Anchors of Carcinoembryonic Antigen Gene Family Members during the Primate Radiation

Abstract

GPI membrane anchors of cell surface glycoproteins have been shown to confer functional properties that are different from their transmembrane (TM)-anchored counterparts. For the human carcinoembryonic antigen (CEA) family, a subfamily of the immunoglobulin superfamily, conversion of the mode of membrane linkage from TM to GPI confers radical changes in function: from tumor suppression or neutrality toward inhibition of differentiation and anoikis and distortion of tissue architecture, thereby contributing to tumorigenesis. We show here that GPI anchorage in the CEA family evolved twice independently in primates, very likely from more primitive TM anchors, by different packages of mutations. Both mutational packages, one package found in many primates, including humans, and a second, novel package found only in the Cebidae radiation of New World monkeys, give rise to efficiently processed GPI-linked proteins. Both types of GPI anchors mediate inhibition of cell differentiation. The estimated rate of nonsynonymous mutations (K a ) in the anchor-determining domain for conversion from TM to GPI anchorage in the CEA family that were fixed during evolution in these primates is 7 times higher than the average K a in primates, indicating positive selection. These results suggest therefore that the functional changes mediated by CEA GPI anchors, including the inhibition of differentiation and anoikis, could be adaptive and advantageous. INTRODUCTIONThe human carcinoembryonic antigen (CEA) family consists of 34 highly similar gene-like sequences, closely clustered on the long arm of chromosome 19, and it includes members made up of amino-terminal V-like Ig domains followed by a variable number of I-like Ig domains and linked to the external cell surface by both GPI and transmembrane (TM) anchors (Zimmermann, personal communication; Hammarström et al., 1998;Zebhauser et al., 2005). GPI-anchored family members CEA and CEACAM6 (formerly NCA) demonstrate radically different functions from TM-linked member CEACAM1 (formerly BGP) in that, when expressed before differentiation, they inhibit the differentiation of many cell types, including myogenic differentiation of rat L6 myoblasts (Eidelman et al., 1993;Screaton et al., 1997), myogenic differentiation of mouse C2C12 cells (Screaton et al., 1997), neurogenic differentiation of retinoic acid-treated mouse P19 EC cells (Malette and Stanners, unpublished data), and adipogenic differentiation of C3H10T1/2 cells (DeMarte and Stanners, unpublished data), whereas CEACAM1 has no such effect (Rojas et al., 1996). They also disrupt cell polarity and tissue architecture of colonic epithelial cells assessed by both in vitro and in vivo assays (Ilantzis et al., 2002). In the latter assays, the ability of CEACAM6-transfected human SW-1222 colonocytes to form colonic crypts with normal architecture in "minicolons" produced under the kidney capsule of the nude mouse was abrogated (Ilantzis et al., 2002). Anoikis, the quality control mechanism that maintains tissue architecture by destroying ...

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