CEACAM1 regulates insulin clearance in liver

Poy, Matthew N.; Yang, Yan; Rezaei, Khadijeh; Fernström, Mats A.; Lee, Abraham D.; Kido, Yoshiaki; Erickson, Sandra K.; Najjar, Sonia M.

doi:10.1038/ng840

Cited by 227 publications

(275 citation statements)

References 42 publications

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“…It was shown that the CEACAM1 protein exhibits antiproliferative properties in carcinomas of colon (24) and prostate (25). Additional data support the central involvement of CEACAM1 in angiogenesis (26), metastasis (27), and insulin clearance (28). CEACAM1 also has a role in the modulation of innate and adaptive immune responses.…”

Section: Inhibition Of Human Tumor-infiltrating Lymphocyte Effector Fmentioning

confidence: 73%

Inhibition of Human Tumor-Infiltrating Lymphocyte Effector Functions by the Homophilic Carcinoembryonic Cell Adhesion Molecule 1 Interactions

Markel

Seidman

Stern

et al. 2006

The Journal of Immunology

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Efficient antitumor immune response requires the coordinated function of integrated immune components, but is finally exerted by the differentiated effector tumor-infiltrating lymphocytes (TIL). TIL cells comprise, therefore, an exciting platform for adoptive cell transfer (ACT) in cancer. In this study, we show that the inhibitory carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) protein is found on virtually all human TIL cells following preparation protocols of ACT treatment for melanoma. We further demonstrate that the CEACAM1 homophilic interactions inhibit the TIL effector functions, such as specific killing and IFN-γ release. These results suggest that CEACAM1 may impair in vivo the antitumor response of the differentiated TIL. Importantly, CEACAM1 is commonly expressed by melanoma and its presence is associated with poor prognosis. Remarkably, the prolonged coincubation of reactive TIL cells with their melanoma targets results in increased functional CEACAM1 expression by the surviving tumor cells. This mechanism might be used by melanoma cells in vivo to evade ongoing destruction by tumor-reactive lymphocytes. Finally, CEACAM1-mediated inhibition may hinder in many cases the efficacy of TIL ACT treatment of melanoma. We show that the intensity of CEACAM1 expression on TIL cells constantly increases during ex vivo expansion. The implications of CEACAM1-mediated inhibition of TIL cells on the optimization of current ACT protocols and on the development of future immunotherapeutic modalities are discussed.

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Section: Inhibition Of Human Tumor-infiltrating Lymphocyte Effector Fmentioning

confidence: 73%

Inhibition of Human Tumor-Infiltrating Lymphocyte Effector Functions by the Homophilic Carcinoembryonic Cell Adhesion Molecule 1 Interactions

Markel

Seidman

Stern

et al. 2006

The Journal of Immunology

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“…CEACAM1 is expressed in epithelia and leukocytes in addition to the endothelia of small angiogenic blood vessels. Furthermore, CEACAM1 is involved in the insulin clearance in the liver (Poy et al, 2002). It was shown that CEACAM1 isoforms are expressed on the surface of Tcells upon activation and are involved in the regulation of Th1-mediated inflammation (Iijima et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

CEA-related cell adhesion molecule-1 is involved in angiogenic switch in prostate cancer

et al. 2006

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We demonstrate here that epithelial carcinoembryonic antigen (CEA)-related cell adhesion molecule-1 (CEA-CAM1) downregulation in prostate intraepithelial neoplasia (PIN) is inversely correlated with its upregulation in adjacent blood vessels. CEACAM1 silencing in prostate cancer cell line DU-145 via small interfering ribonucleic acid (siRNA) increased but its overexpression suppressed the expression of angiogenic/lymphangiogenic factors such as vascular endothelial growth factor (VEGF)-A, -C and -D, and angiogenic inhibitor collagen 18/ endostatin. Furthermore, CEACAM1 overexpression in DU-145 cells increased but CEACAM1 silencing reduced angiopoietin-1 expression. Inverse relation was found for angiopoietin-2. Supernatant of CEACAM1-overexpressing DU-145 suppressed but that of CEACAM1-silenced increased the VEGF-induced endothelial tubes. Electron microscopically the majority of PIN-associated blood vessels was structurally destabilized exhibiting endothelial fenestration, trans-and inter-endothelial gaps. In some PIN areas, invasion of single tumor cells into the destabilized blood vessels was observed. These data show that disappearance of epithelial CEACAM1 in PIN is accompanied by its upregulation in adjacent vasculature which apparently correlates with vascular destabilization and increased vascularization of prostate cancer. Strategies to either conserve the epithelial CEACAM1 or to target endothelial CEACAM1 might be useful for an anti-angiogenic therapy of prostate cancer.

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“…The inhibitory activity of the long cytoplasmic domain is most likely mediated by the binding of Src homology protein-1/2 (SHP-1/2) via its Src homology 2 domains to the phosphorylated ITIM (4,8). A critical Ser residue (S-503 in rat CEACAM1-4L) has also been identified in the long cytoplasmic domain that controls signaling via the insulin receptor in rat hepatocytes (9,10). The 14-aa-short cytoplasmic domain lacks Tyr residues, but can be phosphorylated by protein kinase C on Ser and Thr residues (11) and binds calmodulin (CaM) (11) and both actin and tropomyosin (12).…”

mentioning

confidence: 99%

The Cell-Cell Adhesion Molecule Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 1 Inhibits IL-2 Production and Proliferation in Human T Cells by Association with Src Homology Protein-1 and Down-Regulates IL-2 Receptor

Chen

Shively

2004

The Journal of Immunology

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The cell adhesion molecule, carcinoembryonic Ag-related cellular adhesion molecule 1, shown by others to both activate and inhibit T cell proliferation, exhibits a reciprocal relationship to IL-2R expression over the time course of activation of PBMCs, and upon Ab ligation, inhibits both the production of IL-2 and cell proliferation. Carcinoembryonic Ag-related cellular adhesion molecule 1 associates with CD3 and is found in lipid rafts of PBMCs, is phosphorylated on the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of the -4L isoform, and associates with Src homology protein-1, providing an explanation for its inhibitory activity. When the ITIM-containing -4L and non-ITIM-containing -4S isoforms are transfected into Jurkat cells that produce, but do not depend on IL-2 for growth, both IL-2 production and cell proliferation are differentially inhibited, demonstrating that the two isoforms signal via different pathways. When the two isoforms are transfected into Kit-225 cells that depend on IL-2 for growth, IL-2Rβ and γ, but not α subunits are down-regulated, and the -4L, but not the -4S isoform inhibits cell proliferation by 6-fold in an IL-2 dose-response study.

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CEACAM1 regulates insulin clearance in liver

Cited by 227 publications

References 42 publications

Inhibition of Human Tumor-Infiltrating Lymphocyte Effector Functions by the Homophilic Carcinoembryonic Cell Adhesion Molecule 1 Interactions

Inhibition of Human Tumor-Infiltrating Lymphocyte Effector Functions by the Homophilic Carcinoembryonic Cell Adhesion Molecule 1 Interactions

CEA-related cell adhesion molecule-1 is involved in angiogenic switch in prostate cancer

The Cell-Cell Adhesion Molecule Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 1 Inhibits IL-2 Production and Proliferation in Human T Cells by Association with Src Homology Protein-1 and Down-Regulates IL-2 Receptor

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