CEACAM1 modulates epidermal growth factor receptor–mediated cell proliferation

Abou-Rjaily, George A.; Lee, Sang Jun; May, Denisa; Al-Share, Qusai Y.; DeAngelis, Anthony M.; Ruch, Randall J.; Neumaier, Michael; Kalthoff, Holger; Lin, Sue-Hwa; Najjar, Sonia M.

doi:10.1172/jci21786

Cited by 34 publications

(31 citation statements)

References 51 publications

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“…In Lck-deficient T cells, CEACAM1 cannot be phosphorylated at tyrosine residues and consequently CEACAM1 lacks the ability to associate with SHP-1. This is consistent with previous observations that the tyrosines within the ITIMs of CEACAM1 can be phosphorylated by c-Src kinase in epithelial cells (29,32), Btk kinase in B cells (24), Lyn in neutrophils (38,39), and insulin receptor tyrosine kinase as well as epidermal growth factor receptor tyrosine kinase (40,41). Specific dependence on Lck for CEACAM1 tyrosine phosphorylation in T cells is consistent with a similar role for Lck in mediating tyrosine phosphorylation of Fc␥RIIb in NK cells (42).…”

Section: Discussionsupporting

confidence: 94%

Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits Proximal TCR Signaling by Targeting ZAP-70

Chen

Qiao

et al. 2008

The Journal of Immunology

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The long cytoplasmic tail (CT) isoforms of carcinoembryonic Ag-related cell adhesion molecule 1 (CEACAM1) are expressed on activated human T cells and possess two ITIM motifs in the CT. These isoforms of CEACAM1 are inhibitory for T cell responses initiated by the TCR/CD3 complex with the inhibition dependent upon the ITIMs of CEACAM1 and Src homology 2 domain-containing phosphatase 1 (SHP-1). However, the mechanism by which this inhibition occurs in T cells is unknown. We demonstrate here that the Src family kinase, Lck, and the ability of CEACAM1 to bind homophilically are required for the ITIM phosphorylation of CEACAM1 that is a prerequisite for CEACAM1 association with SHP-1. We further show that CEACAM1 associates with and recruits SHP-1 to the TCR/CD3 complex leading to decreased phosphorylation of CD3-ζ and ZAP-70 and consequently decreased activation of the elements downstream of ZAP-70. This is physiologically relevant because extinction of SHP-1 expression or blockade of homophilic binding by CEACAM1 using a Fab that specifically recognizes the homophilic binding region of human CEACAM1 increases the cytolytic function initiated by the TCR/CD3 complex. These studies show that long CT isoforms of CEACAM1 orchestrate an inhibitory program that abrogates extremely proximal events downstream of the TCR/CD3 complex by focusing on the activation of ZAP-70.

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Section: Discussionsupporting

confidence: 94%

Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits Proximal TCR Signaling by Targeting ZAP-70

Chen

Qiao

et al. 2008

The Journal of Immunology

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“…This is consistent with previous observations that the tyrosines within the CEACAM1-L ITIMs are phosphorylated by c-Src kinase in epithelial cells, Lck kinase in T cells, Btk kinase in B cells, Lyn in neutrophils, and insulin receptor as well as epidermal growth factor receptor tyrosine kinases in hepatocytes (Brummer et al, 1995;Skubitz et al, 1995;Abou-Rjaily et al, 2004;Pantelic et al, 2005;Dubois et al, 2006;Chen et al, 2008;Muller et al, 2009). We have previously shown in a mouse colon tumor model that CEACAM1-L acts as a tumor growth inhibitor.…”

Section: Journal Of Cell Science 123 (24)supporting

confidence: 92%

“…Because CEACAM1-L is phosphorylated by Src-like kinases in epithelial and immune cells (Brummer et al, 1995;Skubitz et al, 1995;Abou-Rjaily et al, 2004;Pantelic et al, 2005;Dubois et al, 2006;Chen et al, 2008;Muller et al, 2009), we looked at whether VEGF-induced CEACAM1-L phosphorylation was elicited by Src kinases in transfected BAECs. To address this, inhibition of Src activity was achieved by pretreating the transfected cells with a specific Src family kinase inhibitor, PP2, before VEGF treatment (Fig.…”

Section: Ceacam1 Is Tyrosine-phosphorylated Upon Vegf Treatment In a mentioning

confidence: 99%

“…CEACAM1 is expressed in a wide range of cells including hematopoietic, epithelial and endothelial cells, where it exerts various biological functions that range from cell adhesion to cell signaling. It affects host immune responses and epithelial integrity as well as maintenance of homeostasis relative to cell proliferation and differentiation (Sadekova et al, 2000;Najjar, 2002;Poy et al, 2002;Fournes et al, 2003;Abou-Rjaily et al, 2004;Gray-Owen and Blumberg, 2006;Leung et al, 2006;Slevogt et al, 2008;Nouvion and Beauchemin, 2009). …”

Section: Introductionmentioning

confidence: 99%

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CEACAM1: a key regulator of vascular permeability

Nouvion

Oubaha

LeBlanc

et al. 2010

Journal of Cell Science

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SummaryCarcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) is an immunoglobulin-like cell surface co-receptor expressed on epithelial, hematopoietic and endothelial cells. CEACAM1 functions as an adhesion molecule, mainly binding to itself or other members of the CEA family. We and others have previously shown that CEACAM1 is crucial for in vivo vascular integrity during ischemic neo-vascularization. Here, we have deciphered the roles of CEACAM1 in normal and pathological vascularization. We have found that Ceacam1-/-mice exhibit a significant increase in basal vascular permeability related to increased basal Akt and endothelial nitric oxide synthase (eNOS) activation in primary murine lung endothelial cells (MLECs). Moreover, CEACAM1 deletion in MLECs inhibits VEGF-mediated nitric oxide (NO) production, consistent with defective VEGF-dependent in vivo permeability in Ceacam1-/-mice. In addition, Ceacam1-null mice exhibit increased permeability of tumor vasculature. Finally, we demonstrate that CEACAM1 is tyrosine-phosphorylated upon VEGF treatment in a SHP-1-and Src-dependent manner, and that the key residues of the long cytoplasmic domain of CEACAM1 are crucial for CEACAM1 phosphorylation and NO production. This data represents the first report, to our knowledge, of a functional link between CEACAM1 and the VEGFR2/Akt/eNOS-mediated vascular permeability pathway.

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“…The Ceacam1 À/À intestinal proliferation index was similar to that of the WT mice ( Figure 1C). CEACAM1-L regulates hepatocyte proliferation through its insulin receptor- (Poy et al, 2002a) and EGFR-mediated-Tyr phosphorylation (Abou-Rjaily et al, 2004) with consequent downregulation of the Ras-mitogen-activated protein kinase (MAPK) signaling. Hence, we monitored Erk activity by determining phospho-ERK expression in the Ceacam1 À/À normal jejunum and ileum ( Figure 1D) and found no significant differences between the WT and CEACAM1-null mice.…”

Section: Resultsmentioning

confidence: 99%

Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1−/− mice

et al. 2008

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The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is downregulated in colonic and intestinal hyperplastic lesions as well as in other cancers, where it functions as a tumor suppressor. To investigate the functions of CEACAM1 in the normal intestine and in intestinal tumors, we generated a compound knockout mouse model and examined both Ceacam1 À/À and Apc 1638N/ þ :Ceacam1 À/À mice. Ceacam1 À/À intestinal cells exhibited a significant decrease in apoptosis, with no change in proliferation or migration, however. Compound Apc 1638N/ þ :Ceacam1 À/À mice demonstrated an increase in intestinal tumor multiplicity and tumor progression. Increases in intussusceptions and desmoid lesions were also observed. We have shown that CEACAM1-L associates with b-catenin by co-immunoprecipitation and colocalization in CEACAM1-L-transfected CT26 and CT51 mouse colon carcinoma cells. Ceacam1 À/À enterocytes displayed decreased glycogen synthase kinase 3-b activity with corresponding nuclear localization of b-catenin. Increased T-cell factor/Lef transcriptional activity was observed in CEACAM1-null CT51 colonic cells and in Caco2 colon cancer cells in which CEACAM1 was downregulated. A significant increased expression in c-Myc and cyclin D1 targets of the Wnt signaling pathway was also revealed in the Ceacam1 À/À intestine. CEACAM1 therefore actively participates in Wnt signaling in intestinal cells and its downregulation in intestinal tissue contributes to malignancy by augmenting tumor multiplicity and progression.

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CEACAM1 modulates epidermal growth factor receptor–mediated cell proliferation

Cited by 34 publications

References 51 publications

Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits Proximal TCR Signaling by Targeting ZAP-70

Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits Proximal TCR Signaling by Targeting ZAP-70

CEACAM1: a key regulator of vascular permeability

Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1−/− mice

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