CD44 - CD44 molecule |Elisa - Clia - Antibody - Protein

Background

CD44 is a type I transmembrane glycoprotein and an important cell surface receptor involved in various physiological and pathological processes. It is expressed on a wide range of cells, including hematopoietic cells, epithelial cells, fibroblasts, endothelial cells, and neurons. CD44 plays a crucial role in cell-cell and cell-matrix interactions, facilitating processes such as cell adhesion, migration, proliferation, and differentiation.

The most well-studied ligand of CD44 is hyaluronic acid (HA), a major component of the extracellular matrix (ECM), which mediates a variety of cellular responses. CD44 is implicated in numerous biological processes, including immune response modulation, tissue repair, inflammation, and cancer metastasis. The molecule is often referred to as a "stem cell marker" due to its elevated expression in several types of cancer stem cells.

CD44 exists in multiple isoforms generated through alternative splicing and post-translational modifications. These isoforms exhibit different functional properties and tissue distributions, further expanding the role of CD44 in diverse biological contexts.

Protein Structure

The CD44 molecule consists of several key structural components:

Extracellular Domain:

• The extracellular region of CD44 is responsible for ligand binding and interaction with components of the extracellular matrix. The most significant binding partner is hyaluronic acid (HA), although CD44 can also interact with other ECM molecules such as collagen, fibronectin, laminin, and osteopontin.
• The N-terminal domain of CD44 contains a link module that is responsible for the high-affinity binding to HA. This domain is homologous to other HA-binding proteins, allowing CD44 to mediate adhesion to HA-rich environments.
• In addition to HA binding, CD44 can undergo extensive glycosylation and sulfation. These post-translational modifications are important for regulating ligand binding affinity and interactions with various ECM components. Glycosylation also contributes to the size heterogeneity of the CD44 protein.

Transmembrane Domain:

• CD44 is anchored to the plasma membrane through a single-pass transmembrane domain. This hydrophobic α-helical region spans the lipid bilayer and serves as a structural anchor for the extracellular domain while also enabling interactions with the intracellular cytoplasmic domain.
• The transmembrane region is important for receptor dimerization or oligomerization, processes that are critical for activating downstream signaling pathways upon ligand binding.

Cytoplasmic Domain:

• The cytoplasmic tail of CD44 is short but plays a pivotal role in signal transduction. It interacts with the intracellular cytoskeleton, particularly through proteins such as ezrin, radixin, and moesin (ERM proteins), linking CD44 to the actin cytoskeleton.
• Through this linkage, CD44 regulates cell shape, migration, and motility. The cytoplasmic domain also interacts with signaling molecules, such as Src family kinases, influencing a variety of intracellular signaling cascades, including those related to cell proliferation, survival, and differentiation.

Classification and Subtypes

CD44 exists in multiple isoforms due to alternative splicing of the CD44 gene. These isoforms are classified into two main categories:

CD44 Standard Isoform (CD44s):

• The standard isoform, CD44s, is the most common form and consists of the constant regions without any additional exon insertions. CD44s is ubiquitously expressed across various cell types and plays a role in basic cellular processes, including cell adhesion, migration, and lymphocyte homing.

CD44 Variant Isoforms (CD44v):

• The CD44 variant isoforms (collectively referred to as CD44v) are generated by alternative splicing, where additional variable exons (v1-v10) are included within the extracellular domain. These variant isoforms are differentially expressed in various tissues and are often associated with specific cellular states, including inflammation, wound healing, and tumor progression.
• Certain CD44v isoforms are frequently overexpressed in cancer cells and are implicated in tumor cell invasion, metastasis, and resistance to apoptosis. For example, CD44v6 and CD44v10 are commonly found in metastatic cancers and are markers for cancer stem cells.

Function and Biological Significance

CD44 plays a multifunctional role in regulating key physiological and pathological processes:

Cell Adhesion and Migration:

• CD44 mediates cell adhesion to the extracellular matrix by binding to hyaluronic acid and other matrix proteins. This adhesion is crucial for maintaining tissue architecture and facilitating cellular movement. CD44 is particularly important in leukocyte homing to sites of inflammation, where it aids in the extravasation of immune cells through endothelial barriers.
• In cancer, CD44 contributes to tumor cell migration and invasion. Its ability to bind HA-rich matrix environments supports the metastatic spread of cancer cells by enhancing their motility and interaction with surrounding tissues.

Cell Proliferation and Survival:

• CD44 signaling influences cell proliferation and survival by interacting with growth factors and activating downstream signaling pathways such as Ras, PI3K/Akt, and MAPK. These pathways are critical for promoting cell division and preventing apoptosis, particularly in stem cells and cancer cells.
• In cancer, CD44-mediated signaling contributes to tumor growth and chemoresistance, making it a target for cancer therapy.

Stem Cell Maintenance:

• CD44 is widely recognized as a stem cell marker, particularly in cancer stem cells. It plays a key role in maintaining stemness properties, including self-renewal and resistance to chemotherapy. CD44-positive cancer stem cells are thought to contribute to tumor recurrence and metastasis following initial treatment.

Immune Response:

• In the immune system, CD44 is critical for the homing and activation of lymphocytes. It facilitates the migration of T cells to inflamed tissues and enhances their activation upon antigen recognition.
• CD44 is also involved in antigen presentation by modulating interactions between T cells and antigen-presenting cells, thereby influencing immune responses.

Wound Healing and Tissue Repair:

• CD44 is important in wound healing and tissue repair processes by regulating the migration of fibroblasts and epithelial cells to the injury site. It also participates in the remodeling of the extracellular matrix during tissue regeneration.

Clinical Issues

The dysregulation of CD44 has been linked to a variety of diseases, most notably cancer, immune disorders, and chronic inflammatory conditions:

Cancer:

• CD44, particularly its variant isoforms, is highly expressed in many types of cancers, including breast, colorectal, lung, and pancreatic cancers. Overexpression of CD44v isoforms is associated with tumor aggressiveness, metastasis, and resistance to chemotherapy. As such, CD44 has emerged as a potential target for cancer therapies aimed at blocking its role in cancer progression.
• CD44-positive cancer stem cells are of particular interest because of their role in promoting tumor recurrence after treatment. Strategies to target CD44-positive cells could enhance the effectiveness of conventional therapies.

Autoimmune Diseases:

• Alterations in CD44 expression have been linked to several autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus (SLE). In these conditions, CD44-mediated cell adhesion and migration contribute to the infiltration of immune cells into affected tissues, exacerbating inflammation.
• Targeting CD44 in these autoimmune conditions has been proposed as a way to reduce immune cell trafficking and alleviate disease symptoms.

Inflammation and Fibrosis:

• CD44 is involved in chronic inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). In these conditions, CD44 promotes the migration of inflammatory cells into the lungs, contributing to tissue damage and fibrosis.
• Therapeutic interventions aimed at blocking CD44-HA interactions may offer potential in treating chronic inflammatory and fibrotic diseases.

Summary

CD44 is a multifunctional transmembrane glycoprotein that plays a critical role in cell adhesion, migration, proliferation, and survival. Its ability to bind hyaluronic acid and other components of the extracellular matrix allows CD44 to regulate key biological processes such as immune response, wound healing, cancer progression, and stem cell maintenance.

Structurally, CD44 consists of an extracellular domain responsible for ligand binding, a transmembrane domain for membrane anchoring and receptor dimerization, and a cytoplasmic domain that links to the actin cytoskeleton and transmits intracellular signals.

The standard isoform (CD44s) is ubiquitously expressed and plays a fundamental role in basic cellular functions, while variant isoforms (CD44v) are associated with specific pathological states, including cancer metastasis and inflammation. CD44 has significant clinical relevance in cancer, autoimmune diseases, and chronic inflammation, making it a promising target for therapeutic intervention.

Understanding the diverse roles of CD44 in health and disease is critical for developing treatments that target its specific functions in different biological contexts.