Self recognition in the Ig superfamily: Identification of precise sub domains in CEA required for intercellular adhesion

Taheri, Maryam Akhavan; Saragovi, Uri; Fuks, Abraham; Makkerh, Joe; Mort, John S.; Stanners, Clifford P.

doi:10.1074/jbc.m909242199

Cited by 43 publications

(57 citation statements)

References 44 publications

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“…Since CD47-expressing cells will only adhere to other CD47-expressing cells, the simplest explanation for the requirement in trans is that CD47 on one cell can interact with CD47 on the apposing cell to mediate adhesion. The kinetics of CD47-dependent cell aggregation are similar to that of the previously described homophilic aggregation responses mediated by other adhesion molecules, such as PECAM-1 (CD31), cadherins, carcinoembryonic antigen related molecules, and CD99 (Xie and Muller, 1993;DeLisser et al, 1994;Taheri et al, 2000;Schenkel et al, 2002). However, unlike these other homophilic interactions, expression of CD47 is not sufficient to induce cell aggregation.…”

Section: Discussionmentioning

confidence: 60%

Novel CD47-dependent intercellular adhesion modulates cell migration

2005

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CD47 is a ubiquitously expressed plasma membrane protein, also known as Integrin Associated Protein, that modulates cell adhesion both through alteration of the avidity of integrin binding and through interaction with its own ligands, the extracellular matrix protein thrombospondin (TSP) and the plasma membrane response regulator SIRPalpha1. We now show that CD47 expression on fibroblasts can induce intercellular adhesion resulting in cell aggregation in the absence of active integrins, SIRPalpha1 binding, and detectable TSP. CD47-expressing cells preferentially bind to other CD47-expressing cells, and intercellular adhesion requires stimulation by serum or a CD47-binding peptide from TSP. Cell-cell adhesion is inhibited by pertussis toxin and C. difficile toxin B, and both adherent and aggregating CD47-expressing fibroblasts have more rac in the GTP bound state than CD47-deficient cells. Spontaneous migration of Jurkat lymphocytes through a fibroblast monolayer is decreased by fibroblast expression of CD47, consistent with an increased barrier function of the CD47 expressing cells. The lymphocyte chemoattractant SDF-1alpha stimulates migration of Jurkat cells through this monolayer only if both the lymphocytes and fibroblasts express CD47, and the inhibition of migration by a CD47-interacting peptide from TSP similarly requires CD47 expression on both cell types. Thus, signaling dependent on both heterotrimeric and rho family GTPases can induce CD47 to participate in cell-cell interactions independent of known ligands that enhance intercellular adhesion and modulate cell migration.

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Section: Discussionmentioning

confidence: 60%

Novel CD47-dependent intercellular adhesion modulates cell migration

2005

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“…More specifically mutagenesis of Arg-43 and Gln-44 on strand CЈ indicate these residues are critical for protection through a process believed to involve dimer formation (31). Val-39 and Asp-40 mutations in the CCЈ loop have also been shown to diminish homophilic dimer formation in fulllength CEACAM1 (32), and this same loop region also seems to be required for intercellular interaction with certain other family members (33). The recent crystal structure, Protein Data Bank (PDB) code 4QXW, as well as 4WHD, provide direct evidence that contacts between the GF loop and adjacent strands, along with CCЈ loop contacts, can form an interface (24).…”

mentioning

confidence: 99%

Glycosylation Alters Dimerization Properties of a Cell-surface Signaling Protein, Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1)

Zhuo

Yang

Moremen

et al. 2016

Journal of Biological Chemistry

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Human carcinoembryonic antigen-related cell adhesion molecule 1 (C?/Au: EACAM1) is a cell-surface signaling molecule involved in cell adhesion, proliferation, and immune response. It is also implicated in cancer angiogenesis, progression, and metastasis. This diverse set of effects likely arises as a result of the numerous homophilic and heterophilic interactions that CEACAM1 can have with itself and other molecules. Its N-terminal Ig variable (Ig V ) domain has been suggested to be a principal player in these interactions. Previous crystal structures of the ␤-sandwich-like Ig V domain have been produced using Escherichia coli-expressed material, which lacks native glycosylation. These have led to distinctly different proposals for dimer interfaces, one involving interactions of ABED ␤-strands and the other involving GFCCC؆ ␤-strands, with the former burying one prominent glycosylation site. These structures raise ques- The human carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) 2 is involved in cell adhesion, proliferation, and immune response (1, 2). It also is implicated in cancer angiogenesis, progression, and metastasis (3). More specifically, it is known that CEACAM1 is a negative-regulator of cell proliferation and is down-regulated in some tumor cells (4 -10). Yet, CEACAM1 expression is reported to protect tumor cells from killing by immune cells (11)(12)(13)(14) and it has been found that the high expression level is associated with a number of other cancers (15)(16)(17)(18)(19). It is likely that this complex set of effects arises as a result of the numerous homophilic and heterophilic interactions that CEACAM1 can have with itself and other members of the CEACAM superfamily. The N-terminal Ig variable (Ig V ) domain of CEACAM1 has been suggested to be the basis of cis and trans homo-dimer formation (20), as well as interactions with other molecules (21-24). There are crystal structures of the Ig V domain expressed in Escherichia coli, which have led to the suggestion of two distinct dimerization interfaces (24, 25). However, examination of the interfaces suggests that the extensive glycosylation found in native material would inhibit dimer formation in one of these cases. This raises questions about the actual type of dimer found in solution, with and without glycosylation. Here, we use NMR methods to examine dimer structures in solution using a non-glycosylated form expressed in E. coli, and several glycosylated variants expressed in HEK293 cells.Dimerization of cell surface molecules is a well accepted mechanism for transmitting signals from the cell surface to the interior (26). In the case of CEACAM1 it is believed that modulation of intercellular adhesion as well as transmission of signals to the cell interior involves switching between cis and trans dimerization interactions. The full-length CEACAM1 molecule is large, sharing a topology with many other cell-surface signaling molecules; the extracellular domain is composed of one Ig V -like domain and typically 3 Ig C2 -like dom...

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“…Taheri and colleagues (20) showed that three short sequences located in the N-domain of the CEACAM5 protein are critical for CEACAM5 homophilic interactions. These short sequences include 30 GYSWYK, 42 NRQII, and 80 QNDTG.…”

Section: Discussionmentioning

confidence: 99%

The Critical Role of Residues 43R and 44Q of Carcinoembryonic Antigen Cell Adhesion Molecules-1 in the Protection from Killing by Human NK Cells

Markel¹,

Gruda²,

Achdout³

et al. 2004

The Journal of Immunology

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The multifunctional carcinoembryonic Ag cell adhesion molecule (CEACAM)1 protein has recently become the focus of intense immunological research. We have previously shown that the CEACAM1 homophilic interactions inhibit the killing activity of NK cells. This novel inhibitory mechanism plays a key role in melanoma immune evasion, inhibition of decidual immune response, and controlling NK autoreactivity in TAP2-deficient patients. These roles are mediated mainly by homophilic interactions, which are mediated through the N-domain of the CEACAM1. The N-domain of the various members of the CEACAM family shares a high degree of similarity. However, it is still unclear which of the CEACAM family members is able to interact with CEACAM1 and what are the amino acid residues that control this interaction. In this study we demonstrate that CEACAM1 interacts with CEACAM5, but not with CEACAM6. Importantly, we provide the molecular basis for CEACAM1 recognition of various CEACAM family members. Sequence alignment reveals a dichotomy among the CEACAM family members: both CEACAM1 and CEACAM5 contain the R and Q residues in positions 43 and 44, respectively, whereas CEACAM3 and CEACAM6 contain the S and L residues, respectively. Mutational analysis revealed that both 43R and 44Q residues are necessary for CEACAM1 interactions. Implications for differential expression of CEACAM family members in tumors are discussed.

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Self recognition in the Ig superfamily: Identification of precise sub domains in CEA required for intercellular adhesion

Cited by 43 publications

References 44 publications

Novel CD47-dependent intercellular adhesion modulates cell migration

Novel CD47-dependent intercellular adhesion modulates cell migration

Glycosylation Alters Dimerization Properties of a Cell-surface Signaling Protein, Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1)

The Critical Role of Residues 43R and 44Q of Carcinoembryonic Antigen Cell Adhesion Molecules-1 in the Protection from Killing by Human NK Cells

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