CD66a CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), BGP (biliary glycoprotein), NCA-160,
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Hematopoietic Cell
T Cell
Liver
Macrophage
Granulocyte
NK Cell
Epithelial Cell
Myeloid Cell
Prostate
140 / 140
180 / 180

Expression
CD66a is expressed on granulocytes and epithelial cells.  Products of 4 of the 7 functional carcinoembryonic antigen (CEA) family genes, CD66a-d, are known to be expressed on hematopoietic cells.  The expression of these molecules on hematopoietic cells is generally restricted to the myeloid lineage.  These molecules are present at low levels on resting mature granulocytes but expression increases rapidly following activation with inflammatory agonists, probably as a result of exocytosis from storage granules.  CD66a is detected on some macrophages in tissue sections and has been reported on T cells and a subpopulation of activated NK cells.  CD66a is also expressed on LAK cells prostate glands and ducts and bile canaliculi between liver cells.  Detection is low on prostatic carcinoma.



Structure
MOLECULAR FAMILY NAME: Belongs to the carcinoembryonic antigen gene family. 

CD66a is a single-pass type-1 glycoprotein.  It contains a 34 aa leader sequence, a 382 aa extracellular domain which contains a N-terminal Ig-like V-type domain and 3 Ig-like C2-type domains, a 43 aa transmembrane and a 67 aa cytoplasmic domain containing 2 YxxL/M motifs and 2 potential tyrosine phosphorylation sites.  The extracellular portions of all CD66 (a-f) molecules possess a N-terminal V-set IgSF domain which, like members of the CD2 family, but lacks the canonical inter-b -sheet disulfide.  CD66a is heavily glycosylated with more than 60% of the mass contributed by N-linked glycans, and they bear sialylated Le x (sLe x, CD15s) structures.  In CD66a they are spaced further apart, VxYxxLx21IxYxxV, and resemble motifs which bind tyrosine phosphatases such as SHIP-1 and-2.  Activation of neutrophils leads to phosphorylation of tyrosine residues in the CD66a cytoplasmic domain.  At least 11 multiple splice variants have been identified for CD66a/BGP.  The CEA family belongs within the Ig gene superfamily.

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Various cells 140-180 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 7 different isoforms. 

POST-TRANSLATIONAL MODIFICATION

CD66a is heavily and variably N-glycosylated, with 20 N-glycosylation sites.

Ligands
CD66 molecules can mediate cell-cell adhesion by homotypic interactions and/or by heterotypic interactions with other CD66 molecules.  CD66a exhibits both heterotypic and homotypic interactions.  The binding sites for these interactions lie within their N-terminal V-set IgSF domains. Unlike most IgSF adhesion molecules, homotypic adhesion involving CD66a is reported both cation and temperature dependent.  CD66a associates with the cytoplasmic tyrosine kinases Src, Lyn and Hck.  Phosphorylated YxxL motifs in the cytoplasmic domain of CD66a bind to the SH2 domain of Src and activate the enzyme.  CD66a associates with CD62E, a mannose-sensitive adhesin of gut bacteria, CD66c and CD66e.

LIGANDS AND MOLECULES ASSOCIATED WITH CD66a
Molecule Comment
CD62 E (E-selectin) CD66a carbohydrate groups interact with CD62 E (E-selectin)
Unknown molecule on bacteria Carbohydrate groups interact with bacteria
CD66a Binds the protein core of CD66a not the carbohydrate
CD66c Binds the protein core of CD66a not the carbohydrate
CD66e Binds the protein core of CD66a not the carbohydrate
Src family kinases Some Src family kinases associate with CD66a neutrophils


CD66a is a receptor of N. gonorrhea.  The CD66 CEA family proteins, specifically CD66a, c, d and e, have recently been reported to function as the receptors which the bacterial species Neisseria gonorrhea and Neisseria meningitidis used to mediate adherence to and cellular invasion of endothelia, epithelia and granulocytic cells.  The differential specificity of distinct phase-variable Opa proteins expressed by these bacteria for individual CD66 members influences both tissue interactions and cellular response to bacterial binding via these receptors.




Function
CD66a is capable of homophilic adhesion, heterophilic adhesion with CD66c and CD66e via their protein core and  E-selectin binding, tumor suppression, type 1 fimbriae binding, transmembrane signaling, granulocyte activation and capable of activating neutrophils.  While the function of CD66a is unclear, the ability of CD66 molecules to mediate cell-cell adhesion and their rapid upregulation following activation suggests that they may contribute to the interactions of activated granulocytes with each other or with the endothelia or epithelia.  However, direct functional evidence for such a role is lacking.  Crosslinking of CD66 molecules with antibodies can stimulate integrin-mediated neutrophil adhesion to endothelial cells, suggesting a possible signaling role.

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD66a IN INTACT ANIMAL

CD66a functions as a receptor for N. gonorrhea and N. meningitides and binds type 1 fimbriae.  Inhibition of CD66a increases apoptotic rate of colon cancer cells and inhibits metastatic tumor growth.  CD66a displays a mannose-sensitive binding to intestinal bacteria and may act as a regulator of bile transport in bile cannaliculi.  Increased serum levels of CD66a are found in individuals suffering from hepatic disorders.


Comments
The CEA family in humans and other mammals.
The human CEA molecules are a family of closely related, IgSF domain-containing glycoproteins encoded by a dense cluster of at least 18 genes within ~1.2 Mb with a 65%-75% sequence identity.  Based on sequence similarity and gene proximity this family can be divided into 2 subgroups, with a 80%-95% sequence identity within each subgroup. The CEA subgroup,  >7 genes, encodes predominantly cell surface molecules, whereas the pregnancy-specific glycoprotein (PSG) subgroup,  >11 genes, encodes secreted molecules.  CEA and PSG subgroups have also been identified in the mouse and the rat.  However, molecules within the subgroups show greater intraspecies,  >80%, than interspecies,  ~60% identity, making it impossible to identify species orthologues.  Indeed orthologues may not exist since sequence analysis suggests that there has been independent and parallel evolution of the CEA and PSG subgroups following the divergence of rodents and humans.

MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD66a
Molecule Comment
Upstream stimulatory factor (USF)
Hepatic nuclear factor 4 (HNF-4)
Ap-2 like factor


SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD66a
Molecule Comment
Src Phosphorylates cytoplasmic domain of CD66a

ADDITIONAL INSIGHTS

The data are consistent with the hypothesis that CD66a plays a signaling role and regulates the adhesion activity of CD11/CD18 in neutrophils. While the details of the "activation signal" transmitted by CD66 antigens are not known, the finding of tyrosine kinases activity associated with CD66a, CD66b and CD66c suggests that these kinase activities may be involved in signal transduction via CD66 family members.  The transient changes in phosphorylation of CD66a in neutrophils following stimulation with chemotactic agents suggest that phosphorylation may be involved in regulating CD66a function as well.  Data also suggest that CD66a is strongly downregulated in malignancies and may have tumor suppressor activity.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 634P13688
Antibodies
YTH71.3   View Reactivity

Revised June 25, 2008


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