CADM1 - Cell Adhesion Molecule with Diverse Functions

CADM1 (Cell Adhesion Molecule 1) is a transmembrane protein belonging to the immunoglobulin superfamily. As a cell adhesion molecule, it plays a vital role in the interaction and adhesion processes between cells and between cells and substrates.

Cell adhesion molecules are a class of proteins located on the cell surface, responsible for facilitating adhesion and interaction between cells and their surroundings. They play crucial roles in regulating cell motility, orientation, signal transduction, and are essential for maintaining tissue structure, supporting development, immune response, and other biological processes.

What is the Immunoglobulin Superfamily?

Immunoglobulin superfamily (IgSF) is a family of proteins widely present in various organisms, and its members have similar structural domains and functions. Proteins of this family typically consist of a series of repeating immunoglobulin domains joined by two beta sheets (beta sheets). The immunoglobulin superfamily plays a variety of important biological functions in the body[1-2].

In the immune system, members of the immunoglobulin superfamily include immunoglobulins (antibodies), T cell receptors, and many ligand receptor molecules[3-4]. Some of these Ig SF members have been identified as biomarkers of cancer progression. For example, MCAM, L1CAM ( CD171 ), NCAM ( CD56 ), PECAM-1 ( CD31 ), ALCAM ( CD166 ) and ICAM-1 ( CD54 ) are associated with different types of cancers such as melanoma, glioma, breast cancer, ovarian cancer, endometrial cancer, prostate cancer and colon cancer [5-6].These proteins bind to antigens or ligands through their structural domains, thereby regulating the immune response of the body. Members of the immunoglobulin superfamily play key roles in antigen recognition, activation and regulation of immune cells, and the formation of immune memory.

What is CADM1?

Structure of CADM1

CADM1, also known as TSLC1, IGSF4, SgIGSF, and SynCAM [7-8], is a member of the immunoglobulin superfamily. It was initially identified as a tumor regulator in small cell lung cancer (SCLC). The CADM1 protein consists of three extracellular immunoglobulin loops, a single transmembrane domain, and a short C-terminal cytoplasmic domain. Within the cytoplasmic domain, there are two conserved protein interaction modules: a 4.1 binding motif and a type II PDZ-binding motif [9]. These modules interact with 4.1 proteins and membrane-associated guanylate kinase homologs (MAGuKs), respectively, playing essential roles in the formation of epithelial cell morphology [10-11], polarity [12-13], and intracellular signal transduction.

Diverse Functions of CADM1

CADM1 plays a crucial role in cell adhesion and interactions, particularly within the nervous system. Here is an in-depth exploration of CADM1's functions:

1. Synapse Formation and Maintenance: In the nervous system, CADM1 serves as an essential cell adhesion molecule involved in synapse formation and maintenance. During early neuron development, CADM1 facilitates interconnection and synapse formation between neurons by binding to other CADM1 proteins and corresponding ligands. This process is vital for establishing neural networks and ensuring effective communication between neurons. Even in adulthood, CADM1 continues to function at synapses, maintaining their structural integrity and proper functioning.
2. Regulation of Neurotransmitter Release: CADM1 also plays a significant role in regulating neurotransmitter release at synapses. By binding to the ligand of the post-synaptic neuron, it can modulate the release of neurotransmitters in the pre-synaptic neuron, thereby influencing the strength and frequency of synaptic transmission. This critical function facilitates the transmission of information between neurons and regulates the overall functioning of neural networks.
3. Cell Adhesion and Immune Regulation: Beyond the nervous system, CADM1 is equally vital in the immune system. In immune cells, CADM1 binds to specific ligands through its extracellular domain, facilitating adhesion and cell-to-cell interactions among immune cells. This process is essential for immune cell activation, proliferation, and the regulation of immune responses.
4. Implications in Tumor Development: CADM1's expression level is found to be up-regulated in certain tumors, and this has been linked to tumor occurrence and development. Research indicates that CADM1 may play a role in the proliferation, invasion, and metastasis of tumor cells. Consequently, its abnormal expression in tumors presents a promising target for tumor therapy and diagnosis.

Mechanisms of CADM1 in Neural Interactions

CADM1's role in cell-cell adhesion and interaction is particularly crucial in the nervous system, where its mechanism of action is complex and involves multiple aspects, including synapse formation, neurotransmitter release, and neural interconnection. The following are the main mechanisms of CADM1 in the nervous system:

1. Synapse Formation: CADM1 plays a pivotal role in synapse formation between neurons. Positioned between presynaptic and postsynaptic neurons, CADM1 binds to other CADM1 proteins and corresponding ligands. This interaction promotes synapse formation on presynaptic and postsynaptic neurons, facilitating neural interconnection and the establishment of synaptic networks.
2. Synapse Maintenance: Beyond synapse formation, CADM1 also maintains the structure and function of mature neuron synapses. By binding to ligands on postsynaptic neurons, it regulates neurotransmitter release from presynaptic neurons, ensuring synaptic stability and normal neurotransmitter transmission.
3. Regulation of Neurotransmitters: CADM1 influences information transmission between neurons by regulating the release of neurotransmitters in presynaptic neurons. In the synaptic area, CADM1 binds to the ligand on the post-synaptic neuron, triggering corresponding signal transduction pathways that regulate neurotransmitter release intensity and frequency. This regulation is critical for functional neural network control.
4. Neural Interconnection: CADM1 expression guides neuron migration and positioning during development, ensuring proper neural interconnection. It plays a guiding role in synapse formation, helping to build accurate neural networks essential for brain function development and maintenance.
5. Interaction with Other Cell Adhesion Molecules: As a cell adhesion molecule, CADM1 interacts with other cell adhesion molecules and extracellular matrix molecules, contributing to cell-cell adhesion and stability and maintaining tissue structure integrity.

CADM1 and tumor immune escape

The relationship between CADM1 and tumor immune escape is a crucial area of interest in tumor biology research. Tumor immune evasion refers to cancer cells evading the surveillance and attack of the immune system, allowing tumors to grow and spread. In this process, tumor cells utilize various mechanisms to suppress or evade the immune system's response, and CADM1 may also play a role in this complex interaction.

CADM1 is typically involved in regulating the adhesion and activation of immune cells. However, in certain tumor types, the expression of CADM1 may change, leading to its association with tumor immune escape. Here are some studies and mechanisms related to CADM1 and tumor immune evasion:

1. Immune Escape and Down-regulation of CADM1: Research has found that in certain tumors, the expression level of CADM1 may be down-regulated. This downregulation weakens the adhesion between immune cells and tumor cells, thereby reducing immune cell attacks on tumors. Additionally, downregulated CADM1 may be associated with tumor cell invasion and metastasis.
2. Immunosuppression-Related Mechanisms: Studies suggest that CADM1 is linked to the regulation of immunosuppressive factors. For instance, tumor cells may inhibit the activation and function of immune cells by influencing the interaction between CADM1 and PD-L1 (Programmed Cell Death Ligand 1). PD-L1 is an immunosuppressive factor, and its combination with PD-1 can hinder T cell activation, preventing immune cells from attacking tumor cells. The interaction of CADM1 and PD-L1 may impact the regulation of this immunosuppressive pathway.
3. Therapeutic Strategies for Tumor Immune Evasion: Researchers are exploring CADM1 and other molecules involved in immune evasion as potential therapeutic targets. Inhibiting the proteins that interact with CADM1 could enhance immune cell attacks on tumor cells, thereby improving the effectiveness of tumor therapy. These studies offer new directions for the development of immunotherapeutic strategies.

The Role of CADM1 in Cancer

CADM1 and Lung Cancer

In lung cancer research, CADM1 plays a critical role in tumor growth, invasion, metastasis, and immune escape. Here are some key associations between CADM1 and lung cancer:

1. Promoting Proliferation and Invasion of Lung Cancer Cells: CADM1 expression is up-regulated in certain types of lung cancer, and this is linked to increased proliferation and invasion capabilities of tumor cells. CADM1 facilitates the growth and invasion of lung cancer cells by participating in cell adhesion and signal transduction, thereby promoting tumor development.
2. Involvement in Tumor Cell Metastasis: CADM1 also plays a vital role in lung cancer metastasis. Studies have shown that high CADM1 expression is associated with lymph node and distant organ metastasis in lung cancer. This suggests that CADM1 may be involved in the migration and metastasis of lung cancer cells.
3. Immune Escape: Abnormal CADM1 expression may contribute to immune escape in lung cancer cells. Tumor cells can evade immune system attacks by regulating the interaction of CADM1 with other immune cells, inhibiting the activation and function of immune cells.
4. Potential Therapeutic Target: Given CADM1's significant role in lung cancer, it is considered a potential therapeutic target. Ongoing studies are exploring CADM1-targeted therapies, such as antibody therapy or small-molecule targeted drugs, to inhibit tumor growth and metastasis.

In lung adenocarcinoma, CADM1 is involved in the Hippo pathway and regulates cell proliferation and contact inhibition. Specifically, CADM1 forms a scaffold protein complex with NF2, KIBRA, SAV1, etc., recruits MST1/2 and LATS1/2 kinases to the cell membrane, and upon phosphorylation, moves to the cytoplasm or nucleus to inactivate YAP1. Activation of the Hippo pathway, in turn, inhibits cell proliferation [15].

CADM1 and pancreatic cancer

CADM1 is also associated with pancreatic cancer, and its abnormal expression may be linked to the onset and progression of the disease. Here are some significant connections between CADM1 and pancreatic cancer:

1. Promotion of Proliferation and Invasion of Pancreatic Cancer Cells: In certain cases of pancreatic cancer, CADM1 expression is found to be up-regulated, contributing to enhanced proliferation and invasion capabilities of tumor cells. By participating in cell adhesion and signal transduction between cells, CADM1 may increase adhesion between pancreatic cancer cells and the basement membrane, thus promoting invasion and metastasis of the tumor.
2. Involvement in Metastasis and Migration of Pancreatic Cancer: Abnormal CADM1 expression may play a role in the metastasis and migration of pancreatic cancer. Changes in its expression level may affect the migration ability of tumor cells, influencing the metastatic process in pancreatic cancer.
3. Correlation with Pancreatic Cancer Prognosis: Research suggests that high CADM1 expression is linked to the prognosis and survival rate of pancreatic cancer. Increased CADM1 expression may be associated with tumor invasion and metastasis, thereby impacting patient prognosis.
4. Potential Therapeutic Target: Given the significant role of CADM1 in pancreatic cancer, it is considered a potential therapeutic target. Ongoing studies are exploring CADM1-targeted therapeutics, such as antibody therapy or small-molecule targeted drugs, to inhibit the growth and metastasis of pancreatic cancer cells.

CADM1 and Gastric Cancer

CADM1 shows a correlation with gastric cancer, a common malignant tumor with a complex pathogenesis involving the abnormal regulation of multiple molecules. Here are some key associations between CADM1 and gastric cancer:

1. Promotion of Proliferation and Invasion of Gastric Cancer Cells: In certain cases of gastric cancer, CADM1 expression is up-regulated, leading to enhanced proliferation and invasion capabilities of tumor cells. By participating in cell adhesion and signal transduction between cells, CADM1 may increase adhesion between gastric cancer cells and the basement membrane, thereby promoting invasion and metastasis.
2. Involvement in Metastasis and Migration of Gastric Cancer: Abnormal CADM1 expression may play a role in the metastasis and migration of gastric cancer. Changes in its expression level can influence the migration ability of tumor cells, impacting the metastatic process in gastric cancer.
3. Clinical Significance: High CADM1 expression is related to the clinical features and prognosis of gastric cancer. Some studies suggest that elevated CADM1 expression may be associated with invasion, metastasis, and poor prognosis in gastric cancer cases.
4. Potential Therapeutic Target: Due to its significant role in gastric cancer, CADM1 is considered a potential therapeutic target. Ongoing studies are exploring CADM1-targeted therapeutics, such as antibody therapy or small-molecule targeted drugs, to inhibit the growth and metastasis of gastric cancer cells.

CADM1 and melanoma

In melanoma, the abnormal expression of CADM1 (Cell Adhesion Molecule 1) has garnered significant research attention. Melanoma is a malignant tumor derived from melanocytes (pigment cells) in the skin and other tissues, characterized by high invasiveness and metastatic potential.

The mechanism and expression of CADM1 in melanoma may involve the following aspects:

1. Promotion of Proliferation and Invasion of Melanoma Cells: Abnormal CADM1 expression may be linked to enhanced proliferation and invasion of melanoma cells. CADM1 potentially increases the adhesion between melanoma cells and the basement membrane by participating in cell-cell adhesion and signal transduction, thereby promoting tumor cell invasion and metastasis.
2. Correlation with Melanoma Prognosis: Studies have found that high CADM1 expression is correlated with the prognosis and survival rate of melanoma. Elevated CADM1 expression may be associated with melanoma invasion and metastasis, ultimately influencing patient prognosis.
3. Potential Therapeutic Target: Given the crucial role of CADM1 in melanoma, it is considered a potential therapeutic target. Researchers are exploring CADM1-targeted therapeutics, such as antibody therapy or small-molecule targeted drugs, to inhibit the growth and metastasis of melanoma cells.

In melanoma, TWIST1 directly inhibits CADM1 expression by interacting with the E-box in the CADM1 promoter region and promotes EMT phenotype conversion, which aggravates migration and invasion of melanoma cells[17]. Moreover, CADM1 acts as an inhibitor of the RAS-RAF-MEK1/2-ERK1/2 pathway and affects TWIST1 activation and the EMT process. In this manner, it regulates invasion and migration of melanoma cells. For high-density cells, increased CADM1 expression inhibits TWIST1 activation and inhibits the EMT process. Furthermore, it promotes cell death under non-adhesive conditions to inhibit tumor metastasis through poly ADP ribose polymerase (PARP)[18-19].

Clinical Prospects of CADM1 in Cancer Research

With a deeper understanding of CADM1's mechanism of action in various cancers, its potential as a therapeutic target and prognostic indicator has gained prominence.

1. Potential Therapeutic Target: Abnormal CADM1 expression is linked to tumor cell proliferation, invasion, and metastasis in different cancers, making it an attractive therapeutic target. Researchers are exploring CADM1-targeted therapies, including antibody therapy and small molecule targeted drugs, to inhibit tumor growth and metastasis effectively.
2. Prognostic Evaluation Indicator: High CADM1 expression is associated with poor prognosis and survival rates in certain cancers. CADM1 could serve as a prognostic indicator, influencing treatment plans and prognoses for cancer patients.
3. Personalized Treatment Strategies: In the era of personalized medicine, tailored treatment strategies for specific cancer patients are crucial. CADM1 expression may vary in different cancer types and patients. Detecting and analyzing CADM1 can help doctors develop personalized treatment plans, leading to improved treatment outcomes.
4. Immunotherapy Potential: Immunotherapy has emerged as a significant advancement in tumor treatment. As CADM1 is related to tumor cell immune escape, studying CADM1 may aid in developing new immunotherapy strategies to enhance the immune system's ability to attack cancer cells.

CADM1 protein:

Recombinant Mouse Cell adhesion molecule 1(Cadm1),partial (Active)

High Purity Validated by SDS-PAGE

Excellent Bioactivity Validated by Functional ELISA

References:

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