CEACAM1 - CEA cell adhesion molecule 1 |Elisa - Clia - Antibody - Protein

Background

CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) is a member of the CEA (carcinoembryonic antigen) family within the immunoglobulin superfamily (IgSF). This molecule plays a central role in intercellular adhesion, immune regulation, and tumor biology. CEACAM1 is highly expressed on various cell types, including epithelial cells, endothelial cells, leukocytes, and certain tumor cells. It is also involved in diverse physiological processes such as cellular differentiation, proliferation, angiogenesis, and immune response modulation.

CEACAM1's expression is tightly regulated, often seen in specific tissues such as the liver, kidneys, and lungs, and it is known to be upregulated during certain immune responses and pathological conditions like inflammation and cancer. This protein has become a subject of interest due to its diverse biological functions, particularly in immune regulation and its role in tumor suppression or tumor progression, depending on the cellular context.

Protein Structure

CEACAM1 is a type I transmembrane glycoprotein that is structurally characterized by a modular composition resembling other members of the IgSF. The molecular structure of CEACAM1 includes the following key domains:

Extracellular Domain:

• The extracellular portion of CEACAM1 is composed of four Ig-like domains:
• The N-terminal IgV-like domain: This domain is primarily responsible for homophilic (CEACAM1-CEACAM1) and heterophilic interactions with other CEACAM family members or external ligands. These interactions are crucial for its role in cell adhesion.
• Three IgC2-like domains: These provide additional structural stability and may also contribute to ligand binding, although they are primarily involved in forming the protein’s overall structure.
• CEACAM1 can exist in two main isoforms, defined by the number of Ig domains: a long isoform (CEACAM1-L) containing four Ig domains and a short isoform (CEACAM1-S) with only one or two Ig domains. The long isoform is more prevalent in immune cells, while the short isoform is often found in epithelial tissues.
• Glycosylation: CEACAM1 is highly glycosylated, with N-linked glycosylation sites present in the Ig-like domains. This glycosylation modulates its interactions with other molecules and is critical for its stability and function in cellular adhesion.

Transmembrane Domain:

• CEACAM1 has a single transmembrane helix that anchors the protein to the plasma membrane. This domain provides stability and also helps in localizing the receptor to specific membrane regions, such as lipid rafts, which are involved in signaling processes.

Cytoplasmic Domain:

The cytoplasmic region of CEACAM1 contains two primary isoforms:

• CEACAM1-L (long): This isoform contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which are critical for signal transduction. Upon phosphorylation of these motifs, CEACAM1-L can recruit SHP-1 and SHP-2 tyrosine phosphatases, leading to downstream signaling that affects various cellular processes, including cell growth, differentiation, and immune modulation.
• CEACAM1-S (short): This isoform lacks the ITIM motifs and thus does not engage in the same downstream signaling pathways as CEACAM1-L. Instead, it is more involved in cell adhesion and structural roles without direct participation in intracellular signaling.

Classification and Subtypes

CEACAM1 belongs to the CEACAM subgroup within the CEA family of proteins. The CEA family includes multiple members like CEACAM3, CEACAM5 (CEA), and CEACAM6, among others, which share structural similarities but have distinct functions. CEACAM1 is distinguished from other members of this family by its role in both immune regulation and cellular adhesion, whereas other CEA family members are more focused on cell adhesion, particularly in epithelial tissues.

CEACAM1 has several isoforms, generated through alternative splicing of the CEACAM1 gene. The most prominent isoforms are:

• CEACAM1-L (long cytoplasmic tail with signaling function)
• CEACAM1-S (short cytoplasmic tail, lacking signaling function)

These isoforms can vary in expression across different tissues and under different physiological or pathological conditions.

Function and Biological Significance

CEACAM1 is a multifunctional protein that plays diverse roles in the body, including cell adhesion, immune regulation, and tumor biology. Its functions can be broadly classified into the following areas:

Cell Adhesion:

• CEACAM1 mediates homophilic (self-self) and heterophilic (self-other) interactions between cells. These interactions are crucial in tissue organization, particularly in epithelial tissues, where CEACAM1 helps maintain tissue architecture and cell polarity. CEACAM1 also plays a role in leukocyte adhesion to the endothelium, contributing to immune cell trafficking and inflammation.

Immune Regulation:

• CEACAM1 is involved in modulating immune responses. The long isoform (CEACAM1-L), with its ITIM motifs, can inhibit immune cell activation through SHP-1/SHP-2 phosphatases, which dephosphorylate key signaling molecules. This helps regulate the immune response, preventing excessive activation and maintaining immune homeostasis.
• CEACAM1 is expressed on T cells, B cells, macrophages, and natural killer (NK) cells, where it influences functions such as T cell activation, B cell differentiation, and cytokine release. It has been implicated in immune tolerance and preventing autoimmunity by dampening overactive immune responses.

Tumor Biology:

• CEACAM1’s role in cancer is complex and context-dependent. In some cancers, it acts as a tumor suppressor, promoting apoptosis, cell differentiation, and inhibition of cell proliferation. However, in other contexts, particularly in more advanced or metastatic tumors, CEACAM1 may promote tumor progression by enhancing immune evasion, angiogenesis, and cell migration.
• The overexpression of CEACAM1 has been noted in several cancers, including melanoma, colorectal cancer, lung cancer, and prostate cancer. In these tumors, CEACAM1 can promote cancer cell adhesion and survival, as well as resistance to immune-mediated killing.

Angiogenesis:

• CEACAM1 is involved in angiogenesis, the formation of new blood vessels. It is expressed on endothelial cells and can modulate the behavior of these cells in response to angiogenic factors such as vascular endothelial growth factor (VEGF). CEACAM1 may play a role in pathological angiogenesis seen in tumor development, promoting the formation of blood vessels that support tumor growth.

Insulin Regulation:

• CEACAM1 has been shown to regulate insulin sensitivity by modulating hepatic insulin clearance. Studies have demonstrated that CEACAM1 is involved in the regulation of insulin receptor signaling in the liver, contributing to glucose homeostasis. Alterations in CEACAM1 function or expression have been linked to insulin resistance and metabolic syndrome, which are risk factors for type 2 diabetes and cardiovascular diseases.

Clinical Issues

Cancer:

• CEACAM1 has been implicated in various malignancies. It may act as either a tumor suppressor or a tumor promoter, depending on the context. In colorectal cancer, for example, the loss of CEACAM1 expression is associated with tumor progression, while in melanoma, overexpression can enhance tumor invasiveness and immune evasion. These findings make CEACAM1 a potential biomarker for cancer progression and a target for cancer therapy.

Autoimmune Diseases:

• CEACAM1’s role in immune regulation suggests it could be involved in the pathogenesis of autoimmune diseases. Its ability to inhibit immune activation may be protective in conditions like autoimmune diabetes or inflammatory bowel disease (IBD), where excessive immune responses target self-tissues.

Metabolic Disorders:

• Altered CEACAM1 expression or function has been linked to metabolic disorders, particularly those involving insulin resistance, such as type 2 diabetes. Studies suggest that CEACAM1 plays a role in regulating hepatic insulin clearance and glucose metabolism, and its dysregulation can contribute to insulin resistance and metabolic syndrome.

Infectious Diseases:

• CEACAM1 is exploited by certain pathogens as a receptor to facilitate infection. For instance, Neisseria gonorrhoeae and Neisseria meningitidis bind to CEACAM1 on mucosal surfaces to invade host tissues, making it a critical factor in susceptibility to infections by these bacteria.

Summary

CEACAM1 (CEA cell adhesion molecule 1) is a multifunctional protein involved in cell adhesion, immune regulation, and tumor biology. Structurally, it belongs to the immunoglobulin superfamily and features multiple extracellular Ig-like domains, a transmembrane region, and cytoplasmic tails that mediate intracellular signaling. Its primary biological functions include mediating cell-cell adhesion, regulating immune responses, promoting angiogenesis, and influencing metabolic processes like insulin sensitivity.

CEACAM1 plays a dual role in cancer, acting as both a tumor suppressor and promoter, depending on the context. It is also implicated in the pathogenesis of autoimmune diseases, metabolic disorders, and infectious diseases. Given its diverse roles, CEACAM1 is of significant interest as both a biomarker and a therapeutic target in various diseases, particularly cancer and metabolic disorders.