Signaling by epithelial members of the CEACAM family – mucosal docking sites for pathogenic bacteria

Abstract

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) comprise a group of immunoglobulin-related vertebrate glycoproteins. Several family members, including CEACAM1, CEA, and CEACAM6, are found on epithelial tissues throughout the human body. As they modulate diverse cellular functions, their signaling capacity is in the focus of current research. In this review we will summarize the knowledge about common signaling processes initiated by epithelial CEACAMs and suggest a model of signal transduction by CEACAM family members lacking significant cytoplasmic domains. As pathogenic and non-pathogenic bacteria exploit these receptors during mucosal colonization, we try to highlight the connection between CEACAMs, microbes, and cellular responses. Special emphasis in this context is placed on the functional interplay between CEACAMs and integrins that influences matrix adhesion of epithelial cells. The cooperation between these two receptor families provides an intriguing example of the fine tuning of cellular responses and their manipulation by specialized microorganisms.

Glycosylation Alters Dimerization Properties of a Cell-surface Signaling Protein, Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1)

“…It is likely that this complex set of effects arises as a result of the numerous homophilic and heterophilic interactions that CEACAM1 can have with itself and other members of the CEACAM superfamily. The N-terminal Ig variable (Ig V ) domain of CEACAM1 has been suggested to be the basis of cis and trans homo-dimer formation (20), as well as interactions with other molecules (21)(22)(23)(24). There are crystal structures of the Ig V domain expressed in Escherichia coli, which have led to the suggestion of two distinct dimerization interfaces (24,25).…”

“…In the case of CEACAM1 it is believed that modulation of intercellular adhesion as well as transmission of signals to the cell interior involves switching between cis and trans dimerization interactions. The full-length CEACAM1 molecule is large, sharing a topology with many other cell-surface signaling molecules; the extracellular domain is composed of one Ig V -like domain and typically 3 Ig C2 -like domains; these are followed by a single transmembrane helix and cytoplasmic tails of different lengths (L and S forms) (20). Hence, subtle changes in the nature of dimerization, which may begin with the Ig V domain, must be transmitted through the entire molecule to reach the cell interior and cytoplasmic tails that contain ITIM signaling motifs.…”

GPI-AP release in cellular, developmental, and reproductive biology

“…Like CEACAM5 and TDGF1, some circulating GPI-APs can be used as clinical biomarkers of disease ( 22,33 ). Because GPIase has substrate specifi city, it could also be a potential target for drug development.…”

“…CEA-related cell-adhesion molecules (CEACAMs) have been implicated in numerous physiological and pathological functions ( 22 ). In humans, there are three major CEACAMs on epithelial tissues: one transmembrane type (CEACAM1) and two GPI-anchored types (CEACAM5 and CEACAM6) ( 23 ).…”

“…CEACAMs may be more important under pathological conditions, as they are bound by various pathogens ( 22 ). CEACAM5 is released by GPLD1-mediated GPI-anchor cleavage ( 25 ); it is overexpressed in many cancers and is a widely used tumor biomarker ( 20,21 ).…”