GPI-anchored CEA family glycoproteins CEA and CEACAM6 mediate their biological effects through activation of integrin α5β1

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.
    Full-text · Article · Apr 2014 · Cell Communication and Signaling
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    • "Whether other molecules that have also been shown to mediate the oncogenic activities of CEACAM6, including fibronectin[22], integrin avb3[14], SMAD3 and TGF-b[23], are also players in the CEACAM6 actions in GC invasion and metastasis remains to be further explored. CEACAM6 is also reported to play immunomodulatory roles in several diseases of human[24]. "
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    ABSTRACT: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) shows increased expression in a wide variety of human cancers, and its over-expression is associated with enhanced migration, invasion, and in vivo metastasis. Here, we reported that CEACAM6 was up-regulated in gastric cancer (GC) cell lines and tumor tissues. Over-expression of CEACAM6 in MKN-45 and SGC-7901 GC cells promoted migration and invasion in vitro and metastasis in athymic mice, whereas migration and invasion of MKN-28 and SNU-16 GC cells were suppressed by knockdown of CEACAM6. We also observed that steroid receptor coactivator (C-SRC) phosphorylation was increased when CEACAM6 was over-expressed in SGC-7901 cells. Taken together, these results suggested that CEACAM6 functions as an oncoprotein in GC and may be an important metastatic biomarker and therapeutic target.
    Preview · Article · Feb 2014 · Acta Biochimica et Biophysica Sinica
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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.
    Full-text · Article · Apr 2008 · Oncogene
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