Anti-CEACAM-1/CD66a

Carcinoembryonic antigen (CEA)-related cell adhesion molecule 1 (CEACAM-1, also called BGP and designated CD66a) is a 160 kDa member of the CEACAM branch of the CEA gene family of the immunoglobulin superfamily. It is one of seven human CEACAM subfamily genes that are essentially divided equally between type I transmembrane proteins (CEACAM-1, 3, and 4) and GPI-linked molecules (CEACAM-5-8). There is no CEACAM-2 in human. The gene for human CEACAM-1 codes for a 526 amino acid (aa) type I transmembrane protein that contains a 34 aa signal sequence, a 394 aa extracellular domain (ECD), a 24 aa transmembrane segment, and a 74 aa cytoplasmic region. The ECD contains one N-terminal V-type Ig-like domain, followed by three C2-type Ig-like domains. It shows considerable glycosylation, including high mannose residues and (sialyl) LewisX. The cytoplasmic region shows one ITIM motif and a calmodulin binding site. In addition to the full length form, ten alternate splice forms have been reported. There are three soluble and seven transmembrane isoforms, with variations occurring in both the ECD and cytoplasmic region. All ten alternate splice forms contain the V-type Ig-like domain (aa's 35-142). The three soluble forms also contain the first two C2-type Ig-like domains (aa's 145-317), with differences coming in the third C2-type Ig-like domain. The seven transmembrane isoforms are highly divergent. Five of the seven contain the V-type plus the first two C2-type domains and then diverge considerably both in the ECD and cytoplasmic region. The remaining two contain only the V-type Ig-like domain, the transmembrane region, and either a full-length or truncated cytoplasmic tail. The actual functions of the isoforms are unclear. Full-length mouse and rat CEACAM-1 are approximately 57% aa identical to human CEACAM-1, in the V-type Ig-like domain, they are 58% and 56% aa identical, respectively. The full-length molecule is found on neutrophils, bile duct epithelium, activated NK cells, colonic columnar epithelium and endothelium. It is known to act as an intercellular adhesion molecule, forming both homotypic, and heterotypic bonds with CEA and CEACAM-6/NCA. On neutrophils, CEACAM-1 also binds to dendritic cell CD-SIGN via its LeX moiety, inducing dendritic cell maturation and a subsequent Th1-type response. Protein function: [Isoform 1]: Cell adhesion protein that mediates homophilic cell adhesion in a calcium-independent manner. Plays a role as coinhibitory receptor in immune response, insulin action and functions also as an activator during angiogenesis (PubMed:16680193, PubMed:17081782, PubMed:18544705, PubMed:21029969, PubMed:21081647, PubMed:22496641, PubMed:22962327, PubMed:23696226). Its coinhibitory receptor function is phosphorylation- and PTPN6 -dependent, which in turn, suppress signal transduction of associated receptors by dephosphorylation of their downstream effectors (PubMed:17081782, PubMed:21029969, PubMed:22496641). Plays a role in immune response, of T-cells, natural killer (NK) and neutrophils (PubMed:17081782, PubMed:21029969, PubMed:22496641, PubMed:23696226). Upon TCR/CD3 complex stimulation, inhibits TCR-mediated cytotoxicity by blocking granule exocytosis by mediating homophilic binding to adjacent cells, allowing interaction with and phosphorylation by LCK and interaction with the TCR/CD3 complex which recruits PTPN6 resulting in dephosphorylation of CD247 and ZAP70 (PubMed:22496641). Also inhibits T-cell proliferation and cytokine production through inhibition of JNK cascade and plays a crucial role in regulating autoimmunity and anti- tumor immunity by inhibiting T-cell through its interaction with HAVCR2 (PubMed:17081782). Upon natural killer (NK) cells activation, inhibit KLRK1-mediated cytolysis of CEACAM1-bearing tumor cells by trans- homophilic interactions with CEACAM1 on the target cell and lead to cis-interaction between CEACAM1 and KLRK1, allowing PTPN6 recruitment and then VAV1 dephosphorylation (PubMed:23696226). Upon neutrophils activation negatively regulates IL1B production by recruiting PTPN6 to a SYK-TLR4-CEACAM1 complex, that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome (PubMed:22496641). Down-regulates neutrophil production by acting as a coinhibitory receptor for CSF3R by downregulating the CSF3R-STAT3 pathway through recruitment of PTPN6 that dephosphorylates CSF3R (PubMed:21029969). Also regulates insulin action by promoting INS clearance and regulating lipogenesis in liver through regulating insulin signaling (PubMed:18544705). Upon INS stimulation, undergoes phosphorylation by INSR leading to INS clearance by increasing receptor-mediated insulin endocytosis. This inernalization promotes interaction with FASN leading to receptor-mediated insulin degradation and to reduction of FASN activity leading to negative regulation of fatty acid synthesis. INSR-mediated phosphorylation also provokes a down-regulation of cell proliferation through SHC1 interaction resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 and phosphatidylinositol 3-kinase pathways. Functions as activator in angiogenesis by promoting blood vessel remodeling through endothelial cell differentiation and migration and in arteriogenesis by increasing the number of collateral arteries and collateral vessel calibers after ischemia (PubMed:16680193, PubMed:22962327). Also regulates vascular permeability through the VEGFR2 signaling pathway resulting in control of nitric oxide production (PubMed:21081647). Down-regulates cell growth in response to EGF through its interaction with SHC1 that mediates interaction with EGFR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (PubMed:15467833). Negatively regulates platelet aggregation by decreasing platelet adhesion on type I collagen through the GPVI- FcRgamma complex (PubMed:19008452). Inhibits cell migration and cell scattering through interaction with FLNA, interferes with the interaction of FLNA with RALA. Mediates bile acid transport activity in a phosphorylation dependent manner. Negatively regulates osteoclastogenesis (PubMed:25490771). [The UniProt Consortium]