A co‐clustering model involving α5β1 integrin for the biological effects of GPI‐anchored human carcinoembryonic antigen (CEA)

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.

Soluble Carcinoembryonic Antigen Activates Endothelial Cells and Tumor Angiogenesis

“…4B and F), was consistent with previous findings that CEA interacts with integrins (14,15). We now observed that CEA led to an increase in integrin ligand-binding activity via enhanced talin/ integrin interaction (Fig.…”

“…Integrin adhesion receptors participate in CEA-induced activation of endothelial cells CEA-mediated modulation of integrin-dependent signal transduction has been reported to occur in tumor cells (14), which seems to be facilitated by colocalization of CEA and integrins in the same subcellular lipid rafts (15). Therefore, we were interested to test a potential role of integrins in CEAinduced endothelial cell activation.…”

“…As CEA is a glycophosphatidylinositol-anchored protein lacking a cytoplasmic domain, transmembrane interaction partners are required for mediating intracellular signal transduction. In this context, a colocalization of CEA with integrins in lipid rafts was observed, which modulated integrin-dependent signaling pathways, including integrin-linked kinase, phosphoinositide 3-kinase (PI3K), and AKT (14,15).…”

Escherichia coliDraE Adhesin-Associated Bacterial Internalization by Epithelial Cells Is Promoted Independently by Decay-Accelerating Factor and Carcinoembryonic Antigen-Related Cell Adhesion Molecule Binding and Does Not Require the DraD Invasin

“…The results imply that integrin recruitment is associated with Dr adhesin-mediated binding to either CEACAMs or DAF. These data are in agreement with published observations demonstrating that CEA clustering by antibodies leads to colocalization of ␣ 5 ␤ 1 integrin in CEA patches on the cell surface (8).…”

CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling

“…CEACAM6 is co-localized to microdomains in the plasma membrane with itself and other CEACAMs [5,6], they can form coclusters activating integrin signaling and its downstream signaling cascades, such as FAK, PI3K/AKT, and MAPK [7][8][9]. GC is one of the most common malignant tumors and a major health burden worldwide [10,11].…”