Transmembrane CEACAM1 affects integrin-dependent signaling and regulates extracellular matrix protein–specific morphology and migration of endothelial cells

Abstract

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1/CD66a), expressed on leukocytes, epithelia, and endothelia mediates homophilic cell adhesion. It plays an important role in cell morphogenesis and, recently, soluble CEACAM1 isoforms have been implicated in angiogenesis. In the present study, we investigated the function of long transmembrane isoform of CEACAM1 (CEACAM1-L) in cultured rat brain endothelial cells. We observed that expression of CEACAM1-L promotes network formation on basement membrane Matrigel and increased cell motility after monolayer injury. During cell-matrix adhesion, CEACAM1-L translocated into the Triton X-100-insoluble cytoskeletal fraction and affected cell spreading and cell morphology on Matrigel and laminin-1 but not on fibronectin. On laminin-1, CEACAM1-L-expressing cells developed protrusions with lamellipodia, showed less stress fiber formation, reduced focal adhesion kinase (FAK) tyrosine phosphorylation, and decreased focal adhesion formation leading to high motility. CEACAM1-L-mediated morphologic alterations were sensitive to RhoA activation via lysophosphatidic acid (LPA) treatment and dependent on Rac1 activation. Furthermore, we demonstrate a matrix protein-dependent association of CEACAM1-L with talin, an important regulator of integrin function. Taken IntroductionCarcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) was originally identified as a homophilic cell-cell adhesion receptor and has been implicated in several cellular functions. 1,2 Studies with epithelial cells revealed the importance of CEACAM1 in cell morphogenesis and proliferation, while analysis of transgenic mice showed a function for CEACAM1 in insulin clearance. [3][4][5] Stimulation of CEACAM antigens in leukocytes modulates signaling and integrin-mediated adhesion. [6][7][8] Apart from its homophilic adhesion capacities, it serves as a receptor for different bacterial strains and for the mouse hepatitis virus. 9,10 This immunoglobulin (Ig)-like molecule is expressed as transmembrane and soluble isoforms. [11][12][13] The cytoplasmic domain of the long isoform of rat CEACAM1 (CEACAM1-L) contains consensus sequences for an immunoreceptor tyrosine-based inhibitory motif (ITIM) 14 and an immunoreceptor tyrosine-based switch motif (ITSM), 15 implicated in signal regulation.In endothelial cells, transmembrane CEACAM1 is found in small blood vessels and capillaries in most mature tissues in the rat and in the developing rat central nervous system, as well as in angiogenic blood vessels. [16][17][18] Angiogenesis is a multistep process that can be roughly divided into 2 phases. In the activation phase, endothelial cells degrade the perivascular basement membrane, migrate into the extracellular space, proliferate, and form capillary sprouts and tubular structures. In the maturation phase, endothelial cells cease migration and proliferation, reconstitute a basement membrane, and recruit smooth muscle cells, thereby permitting the maintenance of vessel wall integrity. 19 Growth fa...

CEACAM1 impedes thyroid cancer growth but promotes invasiveness: a putative mechanism for early metastases

“…Several pathogens have also been shown to engage CEACAM1 in promoting their invasion and colonization of human mucosa (Muenzner et al, 2005). CEACAM1-mediated signaling also promotes network formation on basement membrane and increases endothelial cell motility (Muller et al, 2005).…”

Corticotropin-Releasing Hormone Modulates Human Trophoblast Invasion through Carcinoembryonic Antigen-Related Cell Adhesion Molecule-1 Regulation

“…44 -46 In granulocytes and endothelial cells, CEACAM1 associates with talin, a major cytoskeletal protein implicated in integrin activation. 40,47 Recently, osteopontin, a secreted ECM glycoprotein, and CEACAM1 were suggested to act as a functional complex to enhance invasiveness of trophoblast cells. 48 Thus, CEACAM1 is able to interact and interfere with integrins or integrin-regulated cellular functions and therefore to affect the cellular interactions with the ECM.…”

Deletion of the carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1) gene contributes to colon tumor progression in a murine model of carcinogenesis

“…A number of studies have shown that CEACAM1-L is expressed in newly-forming immature blood vessels of tumors and those resulting from physiological angiogenesis as seen in wound healing and endometrial proliferation (Ergu¨n et al, 2000;Volpert et al, 2002;Oliveira-Ferrer et al, 2004;Muller et al, 2005). As the targeting of Ceacam1 also eliminated the expression of CEACAM1 in endothelial cells, we examined whether the angiogenic properties of the carcinogen-induced tumors was in any way affected by the lack of CEACAM1 expression.…”