Structural aspects of CEACAM1 interactions.

Publisher: Wiley Country of Publication: England NLM ID: 0245331 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2362 (Electronic) Linking ISSN: 00142972 NLM ISO Abbreviation: Eur J Clin Invest Subsets: MEDLINE

Publication: Oxford : Wiley
Original Publication: Berlin, New York, Springer-Verlag, on behalf of the European Society for Clinical Investigation.

Cell Adhesion Molecules*/metabolism ; Cell Adhesion Molecules*/chemistry ; Antigens, CD*/metabolism; Humans ; Protein Binding ; Signal Transduction/physiology

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a membrane protein that plays an important role in a variety of immune and non-immune functions. Such functions are regulated by its activity as a homophilic ligand but also through its ability to interact as a heterophilic ligand with various host proteins. These include CEACAM5, T cell immunoglobulin-mucin like protein-3 (TIM-3) and, potentially, protein death protein 1 (PD-1). Furthermore, CEACAM1 is targeted by various pathogens to allow them to invade a host and bypass an effective immune response. Clinically, CEACAM1 plays an important role in infectious diseases, autoimmunity and cancer. In this review, we describe the structural basis for CEACAM1 interactions as a homophilic and heterophilic ligand. We discuss the regulation of its monomeric, dimeric and oligomeric states in cis and trans binding as well as the consequences for eliciting downstream signalling activities. Furthermore, we explore the potential role of avidity in determining CEACAM1's activities.
(© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Edelman GM, Crossin KL. Cell adhesion molecules: implications for a molecular histology. Annu Rev Biochem. 1991;60:155‐190.
Thiery JP, Brackenbury R, Rutishauser U, Edelman GM. Adhesion among neural cells of the chick embryo. II. Purification and characterization of a cell adhesion molecule from neural retina. J Biol Chem. 1977;252(19):6841‐6845.
Thiery JP, Brackenbury R, Rutishauser U, Edelman GM. Adhesion among neural cells of the chick embryo. Prog Clin Biol Res. 1977;15:199‐206.
Rutishauser U, Thiery JP, Brackenbury R, Edelman GM. Adhesion among neural cells of the chick embryo: III. Relationship of the surface molecule cam to cell adhesion and the development of histotypic patterns. J Cell Biol. 1978;79(2):371‐381.
Rutishauser U, Gall WE, Edelman GM. Adhesion among neural cells of the chick embryo: IV. Role of the cell surface molecule CAM in the formation of neurite bundles in cultures of spinal ganglia. J Cell Biol. 1978;79(2):382‐393.
Brackenbury R, Thiery JP, Rutishauser U, Edelman GM. Adhesion among neural cells of the chick embryo. I. An immunological assay for molecules involved in cell‐cell binding. J Biol Chem. 1977;252(19):6835‐6840.
Cunningham BA. The structure and function of cell adhesion molecules. Adv Mol Cell Biol. 1988;2:25‐54.
Buckley CD, Ed Rainger G, Bradfield PF, Nash GB, Simmons DL. Cell adhesion: more than just glue (review). Mol Membr Biol. 1998;15(4):167‐176.
Chuong CM, Edelman GM. Expression of cell‐adhesion molecules in embryonic induction. I. Morphogenesis of nestling feathers. J Cell Biol. 1985;101(3):1009‐1026.
Janiszewska M, Primi MC, Izard T. Cell adhesion in cancer: beyond the migration of single cells. J Biol Chem. 2020;295:2495‐2505.
Gumbiner BM. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell. 1996;84(3):345‐357.
Zhou H, Fuks A, Stanners CP. Specificity of intercellular adhesion mediated by various members of the immunoglobulin supergene family. Cell Growth Differ. 1990;1(5):209‐215.
Oikawa S, Inuzuka C, Kuroki M, Matsuoka Y, Kosaki G, Nakazato H. Cell adhesion activity of non‐specific cross‐reacting antigen (NCA) and carcinoembryonic antigen (CEA) expressed on CHO cell surface: homophilic and heterophilic adhesion. Biochem Biophys Res Commun. 1989;164(1):39‐45.
Oikawa S, Kuroki M, Matsuoka Y, Kosaki G, Nakazato H. Homotypic and heterotypic Ca++−independent cell adhesion activities of biliary glycoprotein, a member of carcinoembryonic antigen family, expressed on CHO cell surface. Biochem Biophys Res Commun. 1992;186(2):881‐887.
Benchimol S, Fuks A, Jothy S, Beauchemin N, Shirota K, Stanners CP. Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell. 1989;57(2):327‐334.
Tong X, Zou Y. Cell adhesion molecules. In: advances in membrane proteins: building. Signaling and Malfunction. 2019;1:67‐84.
Hintermann E, Christen U. The many roles of cell adhesion molecules in hepatic fibrosis. Cells. 2019;8(12):1503.
Elangbam CS, Ǫualls CW, Dahlgren RR. Cell adhesion molecules—update. Vet Pathol. 1997;34:61‐73.
Harjunpää H, Asens ML, Guenther C, Fagerholm SC. Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment. Front Immunol. 2019;10:1078.
Huang YH, Zhu C, Kondo Y, et al. CEACAM1 regulates TIM‐3‐mediated tolerance and exhaustion. Nature. 2015;517(7534):386‐390.
Kuespert K, Pils S, Hauck CR. CEACAMs: their role in physiology and pathophysiology. Curr Opin Cell Biol. 2006;18(5):565‐571.
Zaidi S, Asalla S, Muturi HT, et al. Loss of CEACAM1 in hepatocytes causes hepatic fibrosis. Eur J Clin Investig. 2024;54(7):e14177.
McCuaig K, Rosenberg M, Nédellec P, Turbide C, Beauchemin N. Expression of the Bgp gene and characterization of mouse colon biliary glycoprotein isoforms. Gene. 1993;127(2):173‐183.
Nédellec P, Turbide C, Beauchemin N. Characterization and transcriptional activity of the mouse biliary glycoprotein 1 gene, a carcinoembryonic antigen‐related gene. Eur J Biochem. 1995;231(1):104‐114.
Gray‐Owen SD, Blumberg RS. CEACAM1: contact‐dependent control of immunity. Nat Rev Immunol. 2006;6:433‐446.
Kim WM, Huang YH, Gandhi A, Blumberg RS. CEACAM1 structure and function in immunity and its therapeutic implications. Semin Immunol. 2019;42:101296.
Beauchemin N, Draber P, Dveksler G, et al. Redefined nomenclature for members of the carcinoembryonic antigen family. Exp Cell Res. 1999;252(2):243‐249.
Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med. 1965;122(3):467‐481.
Harrison PW, Amode MR, Austine‐Orimoloye O, et al. Ensembl 2024. Nucleic Acids Res. 2024;52(D1):891‐899.
Ocklind C, Obrink B. Intercellular adhesion of rat hepatocytes. Identification of a cell surface glycoprotein involved in the initial adhesion process. J Biol Chem. 1982;257(12):6788‐6795.
Svenberg T, Hammarström S, Hedin A. Purification and properties of biliary glycoprotein I (BGP I). Immunochemical relationship to carcinoembryonic antigen. Mol Immunol. 1979;16(4):245‐252.
Svenberg T, Hammarström S, Zeromski J. Immunofluorescence studies on the occurrence and localization of the CEA‐related biliary glycoprotein I (BGP I) in normal human gastrointestinal tissues. Clin Exp Immunol. 1979;36(3):436‐441.
Svenberg T, Hammarström S, Andersson G, Johansson C, Samuelson K, Wahren B. Serum level of biliary glycoprotein i, a determinant of cholestasis, of similar use as γglutamyltranspeptidase. Scand J Gastroenterol. 1981;16(6):817‐824.
Svenberg T. Carcinoembryonic antigen‐like substances of human bile. Isolation and partial characterization. Int J Cancer. 1976;17(5):588‐596.
Svenberg T, Wahren B, Hammarström S. Elevated serum levels of a biliary glycoprotein (BGP I) in patients with liver or biliary tract disease. Clin Exp Immunol. 1979;36(2):317‐325.
Hunter I, Sawa H, Edlund M, Obrink B. Evidence for regulated dimerization of cell‐cell adhesion molecule (C‐CAM) in epithelial cells. Biochem J. 1996;320:847‐853.
Obrink B. On the role of CEACAM1 in cancer. Lung Cancer. 2008;60:309‐312.
Dankner M, Gray‐Owen SD, Huang YH, Blumberg RS, Beauchemin N. CEACAM1 as a multi‐purpose target for cancer immunotherapy. Onco Targets Ther. 2017;6(7):e1328336.
Huang J, Hardy JD, Sun Y, Shively JE. Essential role of biliary glycoprotein (CD66a) in morphogenesis of the human mammary epithelial cell line MCF10F. J Cell Sci. 1999;112(Pt 23):4193‐4205.
Nittka S, Günther J, Ebisch C, Erbersdobler A, Neumaier M. The human tumor suppressor CEACAM1 modulates apoptosis and is implicated in early colorectal tumorigenesis. Oncogene. 2004;23(58):9306‐9313.
Rueckschloss U, Kuerten S, Ergun S. The role of CEA‐related cell adhesion molecule‐ 1 (CEACAM1) in vascular homeostasis. Histochem Cell Biol. 2016;146(6):657‐671.
Ergün S, Kilic N, Ziegeler G, et al. CEA‐related cell adhesion molecule 1: a potent angiogenic factor and a major effector of vascular endothelial growth factor. Mol Cell. 2000;5(2):311‐320.
Singer BB, Scheffrahn I, Kammerer R, Suttorp N, Ergun S, Slevogt H. Deregulation of the CEACAM expression pattern causes undifferentiated cell growth in human lung adenocarcinoma cells. PLoS One. 2010;5(1):e8747.
Ebrahimnejad A, Streichert T, Nollau P, et al. CEACAM1 enhances invasion and migration of melanocytic and melanoma cells. Am J Pathol. 2004;165(5):1781‐1787.
Satoh T, Nakagawa K, Sugihara F, et al. Identification of an atypical monocyte and committed progenitor involved in fibrosis. Nature. 2017;541(7635):96‐101.
Huang YH, Yoon CH, Gandhi A, et al. High‐ dimensional mapping of human CEACAM1 expression on immune cells and association with melanoma drug resistance. Commun Med. 2024;4(1):128.
Li Y, Shively JE. CEACAM1 regulates Fas‐mediated apoptosis in Jurkat T‐cells via its interaction with Β‐catenin. Exp Cell Res. 2013;319(8):1061‐1072.
Terahara K, Yoshida M, Taguchi F, et al. Expression of newly identified secretory CEACAM1a isoforms in the intestinal epithelium. Biochem Biophys Res Commun. 2009;383(3):340‐346.
Gandhi AK, Sun ZYJ, Kim WM, et al. Structural basis of the dynamic human CEACAM1 monomer‐dimer equilibrium. Commun Biol. 2021;4(1):360.
Gandhi AK, Sun ZYJ, Huang YH, et al. Structural analysis of human CEACAM1 oligomerization. Commun Biol. 2022;5(1):1042.
Patel PC, Lee HS, Ming AY, et al. Inside‐out signaling promotes dynamic changes in the carcinoembryonic antigen‐related cellular adhesion molecule 1 (CEACAM1) oligomeric state to control its cell adhesion properties. J Biol Chem. 2013;288(41):29654‐29669.
Klaile E, Vorontsova O, Sigmundsson K, et al. The CEACAM1 N‐terminal Ig domain mediates cis‐ and trans‐binding and is essential for allosteric rearrangements of CEACAM1 microclusters. J Cell Biol. 2009;187:553‐567.
Muller MM, Klaile E, Vorontsova O, Singer BB, Obrink B. Homophilic adhesion and CEACAM1‐S regulate dimerization of CEACAM1‐L and recruitment of SHP‐2 and c‐ Src. J Cell Biol. 2009;187:569‐581.
Wojtowicz WM, Vielmetter J, Fernandes RA, et al. A human IgSF cell‐surface interactome reveals a complex network of protein‐ protein interactions. Cell. 2020;182(4):1027‐1043.e17.
Korotkova N, Yang Y, Le Trong I, et al. Binding of Dr adhesins of Escherichia coli to carcinoembryonic antigen triggers receptor dissociation. Mol Microbiol. 2008;67(2):420‐434.
Kammerer R, Zimmermann W. Coevolution of activating and inhibitory receptors within mammalian carcinoembryonic antigen families. BMC Biol. 2010;8:12.
Hofrichter MAH, Nanda I, Gräf J, et al. A novel de novo mutation in CEACAM16 associated with Postlingual hearing impairment. Mol Syndromol. 2015;6(4):156‐163.
Abou‐Rjaily GA, Lee SJ, May D, et al. CEACAM1 modulates epidermal growth factor receptor–mediated cell proliferation. J Clin Invest. 2004;114:944‐952.
Chen Z, Chen L, Ǫiao SW, Nagaishi T, Blumberg RS. Carcinoembryonic antigen‐related cell adhesion molecule 1 inhibits proximal TCR signaling by targeting ZAP‐70. J Immunol. 2008;180:6085‐6093.
Chen CJ, Shively JE. 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. J Immunol. 2004;172:3544‐3552.
Chen D, Iijima H, Nagaishi T, et al. Carcinoembryonic antigen‐related cellular adhesion molecule 1 isoforms alternatively inhibit and costimulate human T cell function. J Immunol. 2004;172:3535‐3543.
Edlund M, Obrink B. Evidence for calmodulin binding to the cytoplasmic domains of two C‐CAM isoforms. FEBS Lett. 1993;327:90‐94.
Izzi L, Turbide C, Houde C, Kunath T, Beauchemin N. Cis‐determinants in the cytoplasmic domain of CEACAM1 responsible for its tumor inhibitory function. Oncogene. 1999;18:5563‐5572.
Sundberg U, Beauchemin N, Öbrink B. The cytoplasmic domain of CEACAM1‐L controls its lateral localization and the organization pf desmosomes in polarized epithelial cells. J Cell Sci. 2004;117:1091‐1104.
Sundberg U, Öbrink B. CEACAM1 isoforms with different cytoplasmic domains show different localization, organization and adhesive properties in polarized epithelial cells. J Cell Sci. 2002;115(6):1273.
Schumann D, Chen CJ, Kaplan B, Shively JE. Carcinoembryonic antigen cell adhesion molecule 1 directly associates with cytoskeleton proteins actin and tropomyosin. J Biol Chem. 2001;276:47421‐47433.
Chen CJ, Kirshner J, Sherman MA, Hu W, Nguyen T, Shively JE. Mutation analysis of the short cytoplasmic domain of the cell‐cell adhesion molecule CEACAM1 identifies residues that orchestrate actin binding and lumen formation. J Biol Chem. 2007;282(8):5749‐5760.
Chen L, Chen Z, Baker K, et al. The short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction. Immunity. 2012;37(5):930‐946.
Tan K, Zelus BD, Meijers R, et al. Crystal structure of murine sCEACAM1a[1,4]: a coronavirus receptor in the CEA family. EMBO J. 2002;21:2076‐2086.
Obrink B. CEA adhesion molecules: multifunctional proteins with signal‐regulatory properties. Curr Opin Cell Biol. 1997;9:616‐626.
Ghazarian H, Hu W, Mao A, et al. NMR analysis of free and lipid nanodisc anchored CEACAM1 membrane proximal peptides with Ca 2+/CaM. Biochim Biophys Acta Biomembr. 2019;1861(4):787‐797.
Gaur S, Shively JE, Yen Y, Gaur RK. Altered splicing of CEACAM1 in breast cancer: identification of regulatory sequences that control splicing of CEACAM1 into long or short cytoplasmic domain isoforms. Mol Cancer. 2008;7:46.
Singer BB, Scheffrahn I, Obrink B. The tumor growth‐inhibiting cell adhesion molecule CEACAM1 (C‐CAM) is differently expressed in proliferating and quiescent epithelial cells and regulates cell proliferation. Cancer Res. 2000;60:1236‐1244.
Singer BB, Scheffrahn I, Heymann R, Sigmundsson K, Kammerer R, Obrink B. Carcinoembryonic antigen‐related cell adhesion molecule 1 expression and signaling in human, mouse, and rat leukocytes: evidence for replacement of the short cytoplasmic domain isoform by glycosylphosphatidylinositol‐linked proteins in human leukocytes. J Immunol. 2002;168:5139‐5146.
Luo W, Wood CG, Earley K, Hung MC, Lin SH. Suppression of tumorigenicity of breast cancer cells by an epithelial cell adhesion molecule (C‐CAM1): the adhesion and growth suppression are mediated by different domains. Oncogene. 1997;14:1697‐1704.
Markel G, Ortenberg R, Seidman R, et al. Systemic dysregulation of CEACAM1 in melanoma patients. Cancer Immunol Immunother. 2010;59(2):215‐230.
Sivan S, Suzan F, Rona O, et al. Serum CEACAM1 correlates with disease progression and survival in malignant melanoma patients. Clin Dev Immunol. 2012;2012:1‐8.
Ortenberg R, Sapoznik S, Zippel D, et al. Serum CEACAM1 elevation correlates with melanoma progression and failure to respond to adoptive cell transfer immunotherapy. J Immunol Res. 2015;2015:902137.
Liu W. Serum level of CEACAM1 in patients with nonsmall cell lung cancer and its clinical significance in cancer tissue. Journal of healthcare. Engineering. 2022;2022:7948010.
Simeone DM, Ji B, Banerjee M, et al. CEACAM1, a novel serum biomarker for pancreatic cancer. Pancreas. 2007;34:436‐443.
Chothia C, Gelfand I, Kister A. Structural determinants in the sequences of immunoglobulin variable domain. J Mol Biol. 1998;278(2):457‐479.
Hemmingsen JM, Gernert KM, Richardson JS, Richardson DC. The tyrosine corner: a feature of most greek key β‐barrel proteins. Protein Sci. 1994;3(11):1927‐1937.
Gandhi AK, Kim WM, Sun ZYJ, et al. High resolution X‐ray and NMR structural study of human T‐cell immunoglobulin and mucin domain containing protein‐3. Sci Rep. 2018;8:17512.
Zak KM, Kitel R, Przetocka S, et al. Structure of the complex of human programmed death 1, PD‐1, and its ligand PD‐L1. Structure. 2015;23(12):2341‐2348.
Casasnovas JM, Larvie M, Stehle T. Crystal structure of two CD46 domains reveals an extended measles virus‐binding surface. EMBO J. 1999;18(11):2911‐2922.
Wang J, Yan Y, Garrett TPJ, et al. Atomic structure of a fragment of human CD4 containing two immunoglobulin‐like domains. Nature. 1990;348(6300):411‐418.
Belcher Dufrisne M, Swope N, Kieber M, et al. Human CEACAM1 N‐domain dimerization is independent from glycan modifications. Structure. 2022;30:658‐670.
Bonsor DA, Zhao Ǫ, Schmidinger B, et al. The helicobacter pylori adhesin protein HopǪ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA. EMBO J. 2018;37(13):e98664.
Fedarovich A, Tomberg J, Nicholas RA, Davies C. Structure of the N‐terminal domain of human CEACAM1: binding target of the opacity proteins during invasion of Neisseria meningitidis and N. Gonorrhoeae. Acta Crystallogr D Biol Crystallogr. 2006;62:971‐979.
Cheung PH, Luo W, Ǫiu Y, et al. Structure and function of C‐CAM1: the first immunoglobulin domain is required for intercellular adhesion. J Biol Chem. 1993;268(32):24303‐24310.
Wikström K, Kjellström G, Öbrink B. Homophilic intercellular adhesion mediated by C‐CAM is due to a domain 1‐domain 1 reciprocal binding. Exp Cell Res. 1996;227(2):360‐366.
Zhou H, Fuks A, Alcaraz G, Bolling TJ, Stanners CP. Homophilic adhesion between Ig superfamily carcinoembryonic antigen molecules involves double reciprocal bonds. J Cell Biol. 1993;122(4):951‐960.
Teixeira AM, Fawcett J, Simmons DL, Watt SM. The N‐domain of the biliary glycoprotein (BGP) adhesion molecule mediates homotypic binding: domain interactions and epitope analysis of BGPc. Blood. 1994;84:211‐219.
Watt SM, Teixeira AM, Zhou GǪ, et al. Homophilic adhesion of human CEACAM1 involves N‐terminal domain interactions: structural analysis of the binding site. Blood. 2001;98:1469‐1479.
Taheri M, Saragovi U, Fuks A, Makkerh J, Mort J, Stanners CP. Self recognition in the Ig superfamily: identification of precise subdomains in carcinoembryonic antigen required for intercellular adhesion. J Biol Chem. 2000;275(35):26935‐26943.
Markel G, Gruda R, Achdout H, et al. The critical role of residues 43R and 44Ǫ of carcinoembryonic antigen cell adhesion molecules‐ 1 in the protection from killing by human NK cells. J Immunol. 2004;173:3732‐3739.
Bonsor DA, Gunther S, Beadenkopf R, Beckett D, Sundberg EJ. Diverse oligomeric states of CEACAM IgV domains. Proc Natl Acad Sci USA. 2015;112(44):13561‐13566.
Li J, Smolyar A, Sunder‐Plassmann R, Reinherz EL. Ligand‐induced conformational change within the CD2 ectodomain accompanies receptor clustering: implication for molecular lattice formation. J Mol Biol. 1996;263(2):209‐226.
Tingström A, Blikstad I, Aurivillius M, Öbrink B. C‐CAM (cell‐CAM 105) is an adhesive cell surface glycoprotein with homophilic binding properties. J Cell Sci. 1990;96(Pt 1):17‐25.
Xia T, Takagi J, Coller BS, Wang JH, Springer TA. Structural basis for allostery in integrins and binding to fibrinogen‐mimetic therapeutics. Nature. 2004;432(7013):59‐67.
Springer TA. Structural basis for selectin mechanochemistry. Proc Natl Acad Sci USA. 2009;106(1):91‐96.
Lawson EL, Mills DR, Brilliant KE, Hixson DC. The transmembrane domain of CEACAM1‐4S is a determinant of anchorage independent growth and tumorigenicity. PLoS One. 2012;7(1):e29606.
Edlund M, Blikstad I, Obrink B. Calmodulin binds to specific sequences in the cytoplasmic domain of C‐CAM and down‐regulates C‐CAM self‐association. J Biol Chem. 1996;271:1393‐1399.
Najjar SM. Regulation of insulin action by CEACAM1. Trends Endocrinol Metab. 2002;13:240‐245.
Formisano P, Najjar SM, Gross CN, et al. Receptor‐mediated internalization of insulin. Potential role of pp120/HA4, a substrate of the insulin receptor kinase. J Biol Chem. 1995;270:24073‐24077.
Voges M, Bachmann V, Naujoks J, Kopp K, Hauck CR. Extracellular IgC2 constant domains of CEACAMs mediate PI3K sensitivity during uptake of pathogens. PLoS One. 2012;7(6):e39908.
Grasberger B, Minton AP, DeLisi C, Metzger H. Interaction between proteins localized in membranes. Proc Natl Acad Sci USA. 1986;83(17):6258‐6262.
Thompson CJ, Vu VH, Leckband DE, Schwartz DK. Cadherin cis and trans interactions are mutually cooperative. Proc Natl Acad Sci USA. 2021;118(10):e2019845118.
Mukherjee S, Goswami S, Dash S, Samanta D. Structural basis of molecular recognition among classical cadherins mediating cell adhesion. Biochem Soc Trans. 2023;51(6):2103‐2115.
Troyanovsky SM. Adherens junction: the ensemble of specialized cadherin clusters. Trends Cell Biol. 2023;33(5):374‐387.
Jun CD, Shimaoka M, Carman CV, Takagi J, Springer TA. Dimerization and the effectiveness of ICAM‐1 in mediating LFA‐1‐dependent adhesion. Proc Natl Acad Sci USA. 2001;98(12):6830‐6835.
Shapiro L, Fannon AM, Kwong PD, et al. Structural basis of cell‐cell adhesion by cadherins. Nature. 1995;374(6520):327‐337.
Hauck CR, Agerer F, Muenzner P, Schmitter T. Cellular adhesion molecules as targets for bacterial infection. Eur J Cell Biol. 2006;85(3–4):235‐242.
Dash S, Duraivelan K, Samanta D. Cadherin‐mediated host–pathogen interactions. Cell Microbiol. 2021;23(5):e13316.
Pinkert J, Boehm HH, Trautwein M, et al. T cell‐mediated elimination of cancer cells by blocking CEACAM6–CEACAM1 interaction. Onco Targets Ther. 2022;11(1):2008110.
Watt SM, Barker S, Makepeace K, Doyonnas' R, Ferouson DJ, Virjl M. The n‐domain of the human CD66a adhesion molecule is a target for opa proteins of neisseria meningioitis and neisseria gonorrhoeae. Exp Hematol. 1997;25(8):759.
Virji M, Evans D, Hadfield A, Grunert F, Teixeira AM, Watt SM. Critical determinants of host receptor targeting by Neisseria meningitidis and Neisseria gonorrhoeae: identification of Opa adhesiotopes on the N‐domain of CD66 molecules. Mol Microbiol. 1999;34:538‐551.
Conners R, Hill DJ, Borodina E, et al. The Moraxella adhesin UspA1 binds to its human CEACAM1 receptor by a deformable trimeric coiled‐coil. EMBO J. 2008;27:1779‐1789.
van Sorge NM, Bonsor DA, Deng L, et al. Bacterial protein domains with a novel Ig‐like fold target human CEACAM receptors. EMBO J. 2021;40(7):e106103.
Tchoupa AK, Lichtenegger S, Reidl J, Hauck CR. Outer membrane protein P1 is the CEACAM‐binding adhesin of Haemophilus influenzae. Mol Microbiol. 2015;98(3):440‐455.
Moonens K, Hamway Y, Neddermann M, et al. Helicobacter pylori adhesin HopǪ disrupts trans dimerization in human CEACAM s. EMBO J. 2018;37(13):e98665.
Königer V, Holsten L, Harrison U, et al. Helicobacter pylori exploits human CEACAMs via HopǪ for adherence and translocation of CagA. Nat Microbiol. 2016;2:16188.
Brewer ML, Dymock D, Brady RL, Singer BB, Virji M, Hill DJ. Fusobacterium spp. target human CEACAM1 via the trimeric autotransporter adhesin CbpF. J Oral Microbiol. 2019;11(1):1565043.
Klaile E, Müller MM, Schäfer MR, et al. Binding of Candida albicans to human CEACAM1 and CEACAM6 modulates the inflammatory response of intestinal epithelial cells. MBio. 2017;8(2):e02142.
Brümmer J, Ebrahimnejad A, Flayeh R, et al. Cis interaction of the cell adhesion molecule CEACAM1 with integrin β3. Am J Pathol. 2001;159(2):537‐546.
Nonaka M, Ma BY, Murai R, et al. Glycosylation‐ dependent interactions of C‐type lectin DC‐SIGN with colorectal tumor‐associated Lewis glycans impair the function and differentiation of monocyte‐derived dendritic cells. J Immunol. 2008;180(5):3347‐3356.
Anderson AC. Tim‐3: An emerging target in the cancer immunotherapy landscape. Cancer Immunol Res. 2014;2(5):393‐398.
Sakuishi K, Jayaraman P, Behar SM, Anderson AC, Kuchroo VK. Emerging Tim‐3 functions in antimicrobial and tumor immunity. Trends Immunol. 2011;32(8):345‐349.
Zhang D, Jiang F, Zaynagetdinov R, et al. Identification and characterization of M6903, an antagonistic anti–TIM‐3 monoclonal antibody. Onco Targets Ther. 2020;9(1):1744921.
Abdel‐Rahman SA, Ovchinnikov V, Gabr MT. Structure‐based rational Design of Constrained Peptides as TIM‐3 inhibitors. ACS Med Chem Lett. 2024;15(6):806‐813.
Rietz TA, Teuscher KB, Mills JJ, et al. Fragment‐ based discovery of small molecules bound to T‐cell immunoglobulin and mucin domain‐containing molecule 3 (TIM‐3). J Med Chem. 2021;64(19):14757‐14772.
Wu M, Wu A, Zhang X, et al. Identification of a novel small‐molecule inhibitor targeting TIM‐3 for cancer immunotherapy. Biochem Pharmacol. 2023;212:115583.
Ma S, Tian Y, Peng J, et al. Identification of a small‐molecule Tim‐3 inhibitor to potentiate T cell–mediated antitumor immunotherapy in preclinical mouse models. Sci Transl Med. 2023;15(722):eadg6752.
Abdel‐Rahman SA, Talagayev V, Pach S, Wolber G, Gabr MT. Discovery of small‐ molecule TIM‐3 inhibitors for acute myeloid leukemia using pharmacophore‐based virtual screening. J Med Chem. 2023;66(16):11464‐11475.
Huang YH, Zhu C, Kondo Y, et al. Erratum: corrigendum: CEACAM1 regulates TIM‐3‐mediated tolerance and exhaustion. Nature. 2016;536(7616):359.
Zhang Y, Cai P, Li L, et al. Co‐expression of TIM‐3 and CEACAM1 promotes T cell exhaustion in colorectal cancer patients. Int Immunopharmacol. 2017;43:210‐218.
Lake CM, Voss K, Bauman BM, et al. TIM‐3 drives temporal differences in restimulation‐induced cell death sensitivity in effector CD8+ T cells in conjunction with CEACAM1. Cell Death Dis. 2021;12(4):400.
Kojima H, Kadono K, Hirao H, et al. T cell CEACAM1–TIM‐ 3 crosstalk alleviates liver transplant injury in mice and humans. Gastroenterology. 2023;165(5):1233‐1248.
Boulton IC, Gray‐Owen SD. Neisserial binding to CEACAM1 arrests the activation and proliferation of CD4+ T lymphocytes. Nat Immunol. 2002;3:229‐236.
Lee HS, Ostrowski MA, Gray‐Owen SD. CEACAM1 dynamics during neisseria gonorrhoeae suppression of CD4+ T lymphocyte activation. J Immunol. 2008;180:6827‐6835.
Martin JN, Ball LM, Solomon TL, Dewald AH, Criss AK, Columbus L. Neisserial Opa protein‐CEACAM interactions: competition for receptors as a means of bacterial invasion and pathogenesis. Biochemistry. 2016;55(31):4286‐4294.
Sonnert ND, Rosen CE, Ghazi AR, et al. A host–microbiota interactome reveals extensive transkingdom connectivity. Nature. 2024;628(8006):171‐179.
Saiz‐Gonzalo G, Hanrahan N, Rossini V, et al. Regulation of CEACAM family members by IBD‐associated triggers in intestinal epithelial cells, their correlation to inflammation and relevance to IBD pathogenesis. Front Immunol. 2021;12:655960.
Saheb Sharif‐Askari N, Saheb Sharif‐Askari F, Mdkhana B, et al. Enhanced expression of immune checkpoint receptors during SARS‐CoV‐2 viral infection. Mol Ther Methods Clin Dev. 2021;20:109‐121.
Potts M, Fletcher‐Etherington A, Nightingale K, et al. Proteomic analysis of circulating immune cells identifies cellular phenotypes associated with COVID‐19 severity. Cell Rep. 2023;42(6):112613.
ACAR A. Integrative profiling of CEACAM1 in different malignancies with implications on the SARS‐CoV‐2 infection genes ACE2 and TMPRSS2. Hacettepe J Biology and Chemistry. 2023;51(2):215‐225.
Catton EA, Bonsor DA, Herrera C, et al. Human CEACAM1 is targeted by a streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis. Nat Commun. 2023;14(1):2275.
Hsieh YY, Tung SY, Pan HY, et al. Fusobacterium nucleatum colonization is associated with decreased survival of helicobacter pylori‐ positive gastric cancer patients. World J Gastroenterol. 2021;27(42):7311‐7323.
Andersen RN, Ganeshkumar N, Kolenbrander PE. Helicobacter pylori adheres selectively to fusobacterium spp. Oral Microbiol Immunol. 1998;13(1):51‐54.
Livyatan I, Straussman R. A spatial perspective on bacteria in tumours. Nature. 2022;611(7937):674‐675.
Che H, Xiong Ǫ, Ma J, et al. Association of Helicobacter pylori infection with survival outcomes in advanced gastric cancer patients treated with immune checkpoint inhibitors. BMC Cancer. 2022;22(1):904.

R01DK051362 United States DK NIDDK NIH HHS; R01DK051362 United States DK NIDDK NIH HHS

Keywords: CEACAM1; adhesion; host function; immune function

0 (CD66 antigens)
0 (Cell Adhesion Molecules)
0 (Antigens, CD)

Date Created: 20241118 Date Completed: 20241215 Latest Revision: 20241215

20241216

10.1111/eci.14357

39555955