The CEACAM1 N-terminal Ig domain mediates cis- and trans-binding and is essential for allosteric rearrangements of CEACAM1 microclusters

Klaile, Esther; Vorontsova, Olga; Sigmundsson, Kristmundur; Müller, Mario M.; Singer, Bernhard B.; Öfverstedt, Lars-Göran; Svensson, Stina; Skoglund, Ulf; Öbrink, Björn

Adhesion-induced, altered lateral organization of CEACAM1 in the adhesion bridges, manifested as increased parallel dimer formation and smaller clusters, has important implications for the transmembrane signaling by CEACAM1 and suggests a mechanism for how homophilic CEACAM1mediated cell-cell adhesion can influence intracellular signaling. The altered organization of the ectodomains would be transmitted via the transmembrane domains, resulting in a corresponding alteration of the intermolecular organization of the cytoplasmic domains (Fig. 8) . This might in turn influence binding/activation of SH2 domain-carrying enzymes, such as c-Src, SHP-1, and SHP-2, to the tyrosine-phosphorylated cytoplasmic domains of CEACAM1-L, causing a shift in the balance of kinase/phosphatase activation. In the accompanying paper (Müller et al., 2009 ), we demonstrate that such a mechanism involving adhesion-influenced dynamic changes of CEACAM1 microcluster organization indeed exists in epithelial cells.