Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

CEACAMs

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_508

Synonyms

 Bgp;  C-CAM;  CD66

Alternative Names

CEACAM1: Bb-1; Bgp; Bgp1; Bgpa (human); Bgpd (mouse); BGPI; Biliary glycoprotein 1; C-CAM; C-CAM105; NCA-160; nonspecific cross-reacting antigen 160; CD66; CD66a; Cea-1; Cea-7; CEA-related cell adhesion molecule 1; Cea1; Cea7; Carcinoembryonic antigen-related cell adhesion molecule 1; CEACAM1; Ceacam1; mCEA1; MHVR; mmCGM1; mmCGM1a; mmCGM2, CEACAM3: CD66d; CGM1; MGC119875; W264; W282, CEACAM4: CGM7, CEACAM5: CEA; CD66e, CEACAM6: CD66c; NCA; NCA-90; NCA-50/90; CEAL, CEACAM7: CGM2, CEACAM8: CD66b; CD67; CGM6; NCA-95, CEACAM9; CEACAM10; CEACAM11; CEACAM12, CEACAM13, CEACAM14, CEACAM15, CEACAM16, CEACAM17, CEACAM18, CEACAM19, CEACAM20, and CEACAM21: no synonyms

Historical Background

CEA-related cell adhesion molecules (CEACAMs) are members of the carcinoembryonic antigen (CEA) gene family, which belongs to the immunoglobulin superfamily. Two subgroups of the CEA gene family, the CEA-related cell adhesion molecules and the pregnancy-specific glycoproteins (PSGs), are located within a 1.2 Mb cluster on the long arm of human chromosome 19 (19q13.2), the mouse chromosome 7, or the rat chromosome 1 (Kammerer and Zimmermann 2010). All CEACAMs are heavily glycosylated. The CEACAM subgroup in humans consists of 12 members composed of a single immunoglobulin variable (IgV)-like N-terminal (N) domain followed by zero to six Ig constant (IgC)-like domains of A and B subtypes and one member which consists of two IgC-like domains and two IgV-like domains, one at each end of the molecule. Due to its orthologs found in numerous species, CEACAM1 was identified as the ancestral founder molecule of the CEACAM-family (Beauchemin et al. 1999; Beauchemin and Arabzadeh 2013). However, as a result of its early recognition to be a potent tumor marker, CEA/CEACAM5 represents the best-known CEACAM family member (Hammarström 1999; Horst and Wagener 2004). In mice, rats, and cattle, but not in humans, at least two CEACAM1 alleles each have been determined (Kammerer and Zimmermann 2010). Species-specific alternative splicing of several family members further enhances the diversity of the CEACAM family (Singer and Lucka 2005). For example, CEACAM1 mostly appears in at least two coexpressed isoforms one with a long (CEACAM1-L; 73 amino acid), one with a short (CEACAM1-S; 10 amino acid) cytoplasmic tail. The cytoplasmic domain of CEACAM1-L contains tyrosine residues within an immunoreceptor tyrosine inhibition motif (ITIM) that interacts with protein tyrosine kinases of the Src family. CEACAM1, CEACAM3, CEACAM4, CEACAM18, CEACAM19, CEACAM20, and CEACAM21 are transmembrane-anchored molecules while CEA/CEACAM5, CEACAM6, CEACAM7, and CEACAM8 are linked to the cell membrane via glycosylphosphatidylinositol (GPI) anchors, a type of semipenetrating membrane anchorage that exists only in human CEA gene family members. Thus, the variety of CEACAMs expressed in rat and mouse is less (Fig. 1). CEACAM16 represents most likely a secreted molecule. Interestingly, also CEACAM1, CEA/CEACAM5, CEACAM6, and CEACAM8 can appear as secreted variants. The transmembrane-anchored CEACAM17 and the secreted CEACAM9, CEACAM10, CEACAM11, CEACAM12, CEACAM13, CEACAM14, and CEACAM15 exist in rat and mouse but not in human. The transmembrane-bound CEACAM2 is solely found in mice (Beauchemin et al. 1999). Because very little is known about the relatively new discovered CEACAM9-CEACAM21 proteins, this entry will concentrate on CEACAM1-CEACAM8.
CEACAMs, Fig. 1

Domain structure of membrane-anchored members of the CEA gene family expressed in rat, mouse, and human. Each receptor has an amino-terminal IgV-like domain (N domain) followed by a variable number of A or B subsets of IgC2-like domains, a transmembrane and a cytoplasmic domain. Additionally, GPI-anchored CEACAMs appear in human. Alternative spliced variants can be found in some of the CEACAMs and further enhance the complexity of the CEA gene family. CEACAM1 is believed to be the ancestral founder gene of the CEA gene family. The most common isoforms of CEACAM1 carry either a long (CEACAM1–4L) or a short (CEACAM1–4S) cytoplasmic tail. The number of CEACAM1 isoforms varies significantly between the different species. Further information about the CEA gene family can be found at http://www.carcinoembryonic-antigen.de

Expression Patterns of CEACAMs

CEACAMs show a very heterogeneous expression pattern. Thus, CEACAM1 is expressed in several leukocyte-subtypes, most epithelia and endothelia of newly formed small blood vessels (Singer and Lucka 2005). Notably, angiogenically activated microvascular endothelial cells express significant less CEACAM1 than angiogenically activated lymphendothelial cells. The CEACAM1 expression is upregulated in activated granulocytes, B- and T-lymphocytes as well as in confluent, contact-inhibited epithelial cells (Singer and Lucka 2005; Gray-Owen and Blumberg 2006; Singer et al. 2010). Beside the altered CEACAM expression in contact inhibited versus proliferating epithelia cells, the CEACAM1-L to CEACAM1-S ratio can also differ (Singer et al. 2010). The CEACAM3- and CEACAM8-expression is restricted to human granulocytes whereas CEACAM5 and CEACAM7 can solely be found on epithelia. CEACAM6 is expressed in granulocytes and some epithelia. Until now, the expression pattern of CEACAM4 is not finally understood but it is believed to be present in malignant cells of the myeloid lineage and in T- and B-cell lymphoblastic leukemia.

The overexpression of CEA/CEACAM5 in tumors of epithelial origin is the basis of its widespread use as a tumor marker. As a result, the CEA serum levels from individuals with colorectal carcinoma, gastric carcinoma, pancreatic carcinoma, lung carcinoma, breast carcinoma, as well as medullary thyroid carcinoma, and under some nonneoplastic conditions like in ulcerative colitis, pancreatitis, cirrhosis, COPD, Crohn’s disease, and in smokers are usually increased (Hammarström 1999; Horst and Wagener 2004). Also the CEACAM6 expression is significantly upregulated in colon, lung, gastrointestinal, and pancreatic carcinomas. On the contrary, the CEACAM7 expression appears to be decreased in rectal cancer (Horst and Wagener 2004). CEACAM1 can be upregulated or downregulated both in the cancerous tumors. For example, in epithelial tumors of colorectal, liver, breast, prostate, bladder, and renal cancer the CEACAM1 expression level is decreased, whereas in thyroid, gastric, lung cancer as well as in malignant melanoma the CEACAM1 expression is significantly higher (Öbrink 2008). Thus, it is believed that the deregulated expression of CEA/CEACAM5, CEACAM6, CEACAM7, and CEACAM1 is able to provide important tumorigenic contributions to carcinogenesis. However, malignant tumors seem to produce so far unidentified factors that induce microvascular endothelial and lymphendothelial cells to express significant amounts of CEACAM1 (Öbrink 2008). Besides membrane expressed CEACAMs and their soluble variants found in, e.g., sera it was shown that CEACAM1, CEACAM5, and CEACAM6 are also present in tumor-derived microvesicles (Muturi et al. 2013).

The fact that at least two distinct isoforms of CEACAM1, namely, CEACAM1-L and CEACAM1-S, are coexpressed in most if not all cell types enhances the complexity of the CEACAM1 expression pattern. In addition, human CEACAM1 appears with cell type–specific glycosylation levels altering its molecular weight from approximately 120–160 kDa in epithelial cells and granulocytes, respectively (Singer and Lucka 2005).

Functions Mediated by CEACAMs

Members of the CEA family trigger a broad range of diverse functions. It is well established that CEACAM1, CEA/CEACAM5, and CEACAM6 act as cell-cell adhesion molecules (Fig. 2). Either they mediate homophilic adhesion (e.g., CEACAM1 to CEACAM1) or they interact heterophilically by binding to other CEACAMs (e.g., CEACAM1 binds to CEA/CEACAM5 and CEACAM6) (Öbrink 2008). CEACAM1 can bind to membrane-anchored as well as soluble CEACAMs (Öbrink 1997). However, these intercellular adhesive bonds are rather weak and thus CEACAMs most likely represent sensor molecules at the cell surface that regulate cellular signaling. Importantly, the N-domains of CEACAMs are crucial for the homophilic and heterophilic interaction. Furthermore, the N-domains of CEACAM1, CEACAM3, CEACAM5, and CEACAM6 emerged to be pathogen receptors (Fig. 2). It was found that opacity-associated (Opa) proteins of various Neisseria strains, UspA1 molecules of Moraxella catarrhalis, OmpP5 proteins of Haemophilus influenzae and HopQ of Helicobacter pylori specifically ligate to human CEACAMs whereas the Mouse Hepatatis Virus (MHV) solely binds to murine CEACAM1 (Gray-Owen and Blumberg 2006; Slevogt et al. 2008; Tchoupa et al. 2014; Javaheri et al. 2016). Furthermore, in human, CEACAM1 is a receptor for Salmonella and Escherichia coli binds to galectin-3 and to E-selectin via its LewisX and sialyl-LewisX-epitopes latter specifically expressed in CEACAM1 of human granulocytes (Singer and Lucka 2005). It is worth noting that CEACAM ligands like microorganisms, CEACAMs, and CEACAM specific antibodies of one species are not cross-reactive with CEACAMs of any other species.
CEACAMs, Fig. 2

Overview of the extracellular ligands and intracellular interaction partners of CEACAM1-L. Precious few extracellular binding partners exist for CEACAM1. Intracellularly, many different molecules can interact with CEACAM1. Thus the evolutionary pressure toward the extracellular CEACAM1 domains should be less toward its cytoplasmic tail. That notion could explain why CEACAMs expressed in different species share common intracellular binding partners but never extracellular ones

In answer to ligand binding, membrane-anchored CEACAM1 controls apoptosis, cell migration, cell invasion, morphogenesis, insulin metabolism, endocytosis, angiogenesis, lymphangiogenesis, and cell proliferation (Öbrink 2008; Singer and Lucka 2005). Hereby, CEACAM1-L, but not CEACAM1-S, appears to be decisive in mediating these cellular functions (Müller et al. 2009). Thus, in epithelia, CEACAM1-L negatively triggers proliferation via its ITIM domain and maintains the postconfluent contact inhibition, whereas the disturbances of the CEACAM1-L signaling by CEACAM1-4S, CEACAM6, or CEA/CEACAM5 leads to undifferentiated cell growth and malignant transformation (Singer et al. 2010). In agreement with this finding, CEACAM6-overexpressing pancreatic adenocarcinoma cells were more proliferative, more invasive, and more chemoresistant to gemcitabine compared to cells with normal CEACAM6 level (Duxbury et al. 2004). CEACAM6 and CEA/CEACAM5 also were shown to inhibit apoptosis/anoikis further emphasizing their role in promoting aberrant growth (Kuespert et al. 2006).

In immunity, CEACAM1 regulates natural killer cell inhibition, dendritic cell maturation, granulocyte survival, and T and B lymphocyte proliferation and activation (Gray-Owen and Blumberg 2006). Also CEACAM3, CEACAM6, and CEACAM8 are crucial for the regulation of granulocyte activation. Notably, CEACAM8 (CD66b) is a widely utilized differentiation and activation marker for human granulocytes. Recently, it has been shown that several pathogens can diminish the immune response by binding to CEACAM1 on CD4+ T cells as well as in pulmonary epithelial cells via CEACAM1-L(ITIM) mediated signaling (Sadarangani et al. 2010; Slevogt et al. 2008). However, antibodies to CEACAM1 have been reported to increase or decrease T-cell activation in response to T-cell receptor cross-linkage in vitro (Singer and Lucka 2005; Gray-Owen and Blumberg 2006). This apparent discrepancy seems to reflect the different signaling capabilities of CEACAM1 to generate both stimulatory and inhibitory signals via the complex cooperation between the ratio of CEACAM1-L to -S, the equilibrium between monomers, cis- and trans-dimers, levels of phosphorylation, and the interactions with intracellular and cytoskeletal molecules. In contrast, CEACAM3 harbors an immunoreceptor tyrosine-based activation motif (ITAM) within its cytoplasmic tail and is believed to function as a phagocytic receptor involved in the clearance of CEACAM-binding bacteria by human granulocytes (Sadarangani et al. 2010).

Regulation of the Activity of CEACAMs

CEACAMs represent multifunctional adhesion receptor proteins influencing pleiotropic effects in epithelia, endothelia, and hematopoietic cells. The long isoform of CEACAM1 and some other transmembrane-anchored CEA family members can transduce signals directly via their cytoplasmic domains into the cytoplasma. Hereby, CEACAM1-L forms homodimers in a cis-configuration (Öbrink 1997). However, the GPI-linked CEACAMs have a higher lateral mobility in the plasma membrane but need to utilize transmembrane partner molecules like CEACAM1 for signaling. As an example, GPI-linked CEACAMs are able to alter the CEACAM1-L maintained postconfluent contact inhibition (Singer et al. 2010). In addition, CEACAM1-S can interfere with the CEACAM1-L mediated functions most likely via cis-dimerization (Öbrink 1997). Thus, the ratio of CEACAM1-L to CEACAM1-S possibly together with additionally coexpressed CEA family members seems to be decisive for the functional outcome mediated by CEACAM1 (Singer et al. 2010).

The homophilic and heterophilic adhesion of CEACAM1 and other CEACAMs as well as pathogen binding is mediated by N-terminal domain interactions (Öbrink 1997). The ligand binding induces signal cascades starting with the phosphorylation of distinct tyrosine residues within the cytoplasmic tail of the transmembrane-anchored CEACAMs (Fig. 3). Human CEACAM1 contains two ITIM in its cytoplasmic domain, whereas in rodents one CEACAM1 ITIM is replaced by an immunoreceptor tyrosine-based switch motif (ITSM) (Kammerer and Zimmermann 2010). Human CEACAM3 and probably CEACAM4, CEACAM19, and CEACAM20 carry ITAM in their cytoplasmic tails. In contrast, except for CEACAM19 and CEACAM20 no such ITAM-containing CEA family members exist in rodents. It is general accepted that the phosphorylation of the tyrosine residues within the ITIM represents the initial step of CEACAM1 mediated signaling. CEACAM1-L can be phosphorylated by protein tyrosine kinases of the  Src family, by the insulin receptor kinase (IR), and by the epithelial growth factor receptor (EGFR) (Öbrink 1997; Singer and Lucka 2005). Upon phosphorylation, CEACAM1-L can bind and activate both protein tyrosine kinases (such as c-src, lyn, and hck) and protein tyrosine phosphatases such as SHP-1 and SHP-2 (Singer and Lucka 2005).
CEACAMs, Fig. 3

Initial steps of the CEACAM1-L mediated signaling. Ligation of CEACAM1-L triggers the tyrosine phosphorylation within its cytoplasmic ITIM and the recruitment of SHP-1. Subsequently, CEACAM1 can interact via SHP-1 with other receptors and modulate their signaling capacity and thus influence the functional outcome

Besides CEACAM1-L, CEACAM1-S has the potential to directly induce signal transduction. Thus, protein kinase C (PKC) can phosphorylate the serine and threonine residues of CEACAM1-S and -L (Singer and Lucka 2005; Müller et al. 2009). Additionally, both splice variants interact with the DNA polymerase delta-interacting protein 38 (Poldip 38) (Klaile et al. 2007) as well as with actin, talin, paxillin, and filamin A (Fig. 2) (Singer and Lucka 2005). The PKC-mediated phosphorylation of CEACAM1 induces calmodulin binding to the cytoplasmic domain of CEACAM1 and as a result regulates its cis-dimerization (Klaile et al. 2009). CEACAM1 associates also in cis with integrin αvβ3 probably to promote cellular invasion (Singer and Lucka 2005). Moreover, CEACAM3 is phosphorylated within its ITAM by Src-kinases, in particular Hck and Fgr (Kuespert et al. 2006). This phosphorylation is triggered by bacterial binding stimulating in the following the small GTPases Rac. Consequently, the pathogen becomes phagocytozed and killed. In addition, there are reports showing that GPI-anchored members of the CEA family are able to induce signal transduction. Thus, ligation of CEACAM8 leads to an activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) and the overexpression of CEACAM6 leads to an increased activity of the tyrosine kinase c-Src and the serine/threonine kinase akt-1 (Singer et al. 2002; Duxbury et al. 2004). Furthermore, CEACAM6 and CEACAM8 (as well as CEACAM1 and CEACAM3) can initiate adhesion of neutrophilic granulocyte to endothelial cells most likely by activating integrins (Singer and Lucka 2005). Although it is not finally understood how GPI-anchored CEACAMs manage to kick off their signaling cascades, it is likely that they employ CEACAM1 or other transmembrane molecules for signaling.

In recent times, several groups have demonstrated that CEACAM1 acts as a coreceptor of numerous cell receptors (Fig. 3). In lymphendothelial cells membrane-bound CEACAM1 mediates proangiogenic functions by interfering with the vascular endothelial growth factor receptor-3 (VEGFR-3) (Kilic et al. 2007). Hereby, CEACAM1-L(ITIM) is tyrosine-phosphorylated upon VEGF treatment in a SHP-1- and Src-dependent manner. Lately, CEACAM1 was shown to be coreceptor of the VEGFR-2 regulating the VEGFR2/Akt/eNOS-mediated vascular permeability pathway and angiogenesis (Nouvion et al. 2010). Furthermore, under certain circumstances IR and EGFR are able to phosphorylate Tyr-488 of the CEACAM1-L(ITIM). Subsequently, the SH2 domain of the Src homology 2 domain-containing transforming protein 1 (Shc) can associate leading to decreased Ras/MAPK Erk1/2 pathway induction (Kuespert et al. 2006). As a result, CEACAM1 negatively regulates cell proliferation in response to insulin and EGF, respectively. Moreover, various antibodies to CEACAM1 have been reported to enhance or diminish T-cell activation in response to ligation of the T-cell receptor (TCR) (Singer and Lucka 2005). However, in activated CD4+ T-lymphocytes, CEACAM1 appeared to be an inhibitory coreceptor of the TCR/CD3 complex. CEACAM1-L(ITIM) phosphorylation and subsequent association with SHP-1 were identified as the initiating signaling steps. Afterward, CEACAM1 interacts via SHP1 with the TCR/CD3 complex, which leads to decreased CD3-zeta, ZAP-70, and IL2-R signaling (Gray-Owen and Blumberg 2006; Sadarangani et al. 2010). Similar to its function as coreceptor for the TCR, CEACAM1 was described to function as an inhibitory comodulator of the human B cell receptor (BCR), likely through the recruitment of SHP-1 and inhibition of the phosphatidylinositol 3-OH kinase–Akt kinase (PI3K)-promoted pathway (Lobo et al. 2009). In contrast, other studies showed that certain CEACAM1-specific monoclonal antibodies or the homophilic CEACAM1-CEACAM1 interaction strongly triggered the proliferation of mouse B cells when combined with the ligation of the BCR (Greicius et al. 2003). Furthermore, CEACAM1 was shown to be a crucial regulator of the B-cell survival, influencing both B-cell numbers and protective antiviral antibody responses (Khairnar et al. 2015). CEACAM1 acts also as coinhibiting receptor of the Toll-like receptor 2 (TLR2). The inhibitory effects were mediated by tyrosine phosphorylation of CEACAM1-L(ITIM) and recruitment of SHP-1, which negatively regulates the TLR2-dependent activation of the PI3K activation pathway and the initiation of the NF-kappa B-dependent inflammatory responses (Slevogt et al. 2008). Consequently, the generation and release of proinflammatory cytokines such as GM-CSF and IL8 were reduced. Last but not least, CEACAM1 was described to be a coinhibitory receptor molecule for the granulocyte colony-stimulating factor receptor (G-CSFR) regulating granulopoiesis through CEACAM1-L(ITIM) phosphorylation and SHP-1 interaction leading to decreased Stat3 activation (Pan and Shively 2010).

Summary

CEACAMs are members of the CEA-gene family. Nowadays, the CEACAM1 to CEACAM8 are well analyzed whereas very little is known about CEACAM9 to CEACAM21. The CEACAM1 to CEACAM8 expression pattern varies considerably in accordance with the species, the cell type, the cell growth, and activation state. Notably, the CEACAM expression is frequently deregulated in many types of cancer indicating their putative role in tumor-growth regulation. However, most membrane-bound CEACAMs function as cell-adhesion receptor molecules mediating a broad range of functions including apoptosis, cell migration, cell invasion, contact-inhibition, morphogenesis, insulin metabolism, endocytosis, angiogenesis, lymphangiogenesis, and cell proliferation. In addition, CEACAM1 was found to be a crucial coreceptor for TCR, BCR, TLR-2, IR, EGFR, G-CSFR, VEGFR-2, and VEGFR-3. CEACAM1 interacts with diverse signal transducing proteins depending on its phosphorylation stage. Some CEACAMs were also identified to bind species specific certain pathogens like Moraxella catarrhalis or Neisseria gonorrhoeae. Thus, CEACAMs seem to play a central role in controlling pathogens by the innate immune system. Furthermore, a putatively pathogen driven evolution of the CEA gene family could be responsible for the high variability of the number of diverse CEACAMs expressed in the different species. However, more knowledge is needed about the abundance of CEACAM1, the relative proportion of CEACAM1-L to CEACAM1-S isoforms, and the appearance of further coexpressed CEACAMs to fully understand the signaling and functional potential of members of the CEA family.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of AnatomyUniversity Hospital Essen, University of Duisburg-EssenEssenGermany