GPI-anchored CEA family glycoproteins CEA and CEACAM6 mediate their biological effects through enhanced integrin α5β1-fibronectin interaction

Department of Biochemistry and McGill Cancer Centre, McGill University, Montreal, Quebec, Canada.
Journal of Cellular Physiology (Impact Factor: 3.84). 03/2007; 210(3):757-65. DOI: 10.1002/jcp.20887
Source: PubMed


Carcinoembryonic antigen (CEA) and CEA family member CEACAM6 are glycophosphatidyl inositol (GPI)-anchored, intercellular adhesion molecules that are up-regulated in a wide variety of human cancers, including colon, breast, and lung. When over-expressed in a number of cellular systems, these molecules are capable of inhibiting cellular differentiation and anoikis, as well as disrupting cell polarization and tissue architecture, thus increasing tumorigenicity. The present study shows that perturbation of the major fibronectin receptor, integrin alpha5beta1, underlies some of these biological effects. Using confocal microscopy and specific antibodies, CEA and CEACAM6 were demonstrated to co-cluster with integrin alpha5beta1 on the cell surface. The presence of CEA and CEACAM6 was shown to lead to an increase in the binding of the integrin alpha5beta1 receptor to its ligand fibronectin, without changing its cell surface levels, resulting in increased adhesion of CEA/CEACAM6-expressing cells to fibronectin. More tenacious binding of free fibronectin to cells led to enhanced fibronectin matrix assembly and the formation of a polymerized fibronectin "cocoon" around the cells. Disruption of this process with specific monoclonal antibodies against either fibronectin or integrin alpha5beta1 led to the restoration of cellular differentiation and anoikis in CEA/CEACAM6 producing cells.

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Available from: Maria del Pilar Camacho Leal, May 13, 2015
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    • "Since ligand-bound integrins locally organize membrane microdomains, they could constitute a co-receptor for epithelial CEACAMs [85,86]. Indeed, the observed functional co-operation was suggested to result from co-clustering of GPI-linked CEACAMs together with integrins in these membrane areas [87]. A co-operation between CEACAMs and integrins would nicely explain the modulation of cellular functions such as cell adhesion and cell survival in the absence of matrix-attachment [88,89]. "
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    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.
    Cell Communication and Signaling 04/2014; 12(1):27. DOI:10.1186/1478-811X-12-27 · 3.38 Impact Factor
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    • "Our previous evidence supported a model for CEA signaling in which clustering of CEA GPI anchors in lipid rafts leads to a5 integrin clustering and activation followed by activation of the PI3-K/Akt and MAPK signaling pathways (Camacho-Leal et al., 2007). Indeed, in colonic cells, we have shown that perturbation of a5 integrin–ECM interaction reversed the CEA-mediated anoikis inhibition (Ordonez et al., 2007). The role of the PI3-K/Akt and MAPK cascades in cell survival mechanisms has been extensively documented (Frisch and Screaton, 2001). "
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    ABSTRACT: Human carcinoembryonic antigen (CEA) is a cell surface adhesion molecule member of the Immunoglobulin Superfamily (IgSF). Aberrant upregulation of CEA is a common feature found in a wide variety of human cancers such as colon, breast and lung. Previous in vitro and in vivo results have demonstrated that CEA can have tumorigenic effects including the inhibition of cell differentiation and anoikis, a specific type of apoptosis triggered by the absence of extracellular matrix-cell contacts. In the present work, we investigate the involvement of the caspase cascade in CEA-mediated inhibition of anoikis and the structural requirements for this signal. Expression of CEA and/or a chimeric protein consisting of the NCAM extracellular domain attached to the CEA-GPI anchor correlates with an early inactivation of caspase-9 and activation of the PI3-K/Akt survival pathway, and at later times, inactivation of caspase-8. The CEA-mediated caspase inactivation as well as activation of Akt was not observed by expression of a CEA molecule incapable of self-binding (DeltaNCEA). These results suggest that the intrinsic caspase pathway is involved in the inhibitory effects of anoikis by CEA and this signal is dependent on the presence of self-adhesive extracellular domains and a CEA-GPI anchor.
    Oncogene 04/2008; 27(11):1545-53. DOI:10.1038/sj.onc.1210789 · 8.46 Impact Factor
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    • "The effects of MAPK localization and activation were reproducible at least in three independent experiments. Huang et al., 2000) led to the hypothesis that ILK could be a component of the CEA-induced signal transduction pathway since, as for these previous observations, the forced expression of CEA in both mouse C2C12 and L6 myoblasts inhibits myogenic differentiation (Screaton et al., 1997), inhibits anoikis in many cell types including human colonocytes and L6 myoblasts (Ordonez et al., 2000) and increases fibronectin matrix assembly (Ordonez et al., 2007). Consistent with previous results (Delcommenne et al., 1998; Troussard et al., 2003), we identified ILK and Akt as downstream targets of PI3-K, since inhibition of PI3-K prevented ILK localization to membrane microdomains (Fig. 5B) and Akt phosphorylation (Fig. 5A,C). "
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    ABSTRACT: CEA functions as an intercellular adhesion molecule and is up-regulated in a wide variety of human cancers, including colon, breast and lung. Its over-expression inhibits cellular differentiation, blocks cell polarization, distorts tissue architecture, and inhibits anoikis of many different cell types. Here we report results concerning the molecular mechanism involved in these biological effects, where relatively rapid molecular changes not requiring alterations in gene expression were emphasized. Confocal microscopy experiments showed that antibody-mediated clustering of a deletion mutant of CEA (DeltaNCEA), normally incapable of self binding and clustering, led to the co-localization of integrin alpha5beta1 with patches of DeltaNCEA on the cell surface. Activation of alpha5, as defined by an anti-alpha5 mAb-sensitive increase in cell adhesion to immobilized fibronectin, and an increased binding of soluble fibronectin to cells, was also observed. This was accompanied by the recruitment of integrin-linked kinase (ILK), protein kinase B (PKB/Akt), and the mitogen-activated protein kinase (MAPK) to membrane microdomains and the phosphorylation of Akt and MAPK. Inhibition of PI3-K and ILK, but not MAPK, prevented the alpha5beta1 integrin activation. Conversely, anti-alpha5 antibody inhibited the PI3-K-mediated activation of Akt, implying the involvement of outside-in and inside-out signaling in integrin activation. Therefore we propose that CEA-mediated signaling involves clustering of CEA and co-clustering and activation of the alpha5beta1 and associated specific signaling elements on the internal surfaces of membrane microdomains. These changes may represent a molecular mechanism for the biological effects of CEA.
    Journal of Cellular Physiology 06/2007; 211(3):791-802. DOI:10.1002/jcp.20989 · 3.84 Impact Factor
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