CD9 - CD9 molecule |Elisa - Clia - Antibody - Protein

Background

CD9 is a member of the tetraspanin superfamily, a group of transmembrane proteins involved in various biological processes, particularly in cell adhesion, migration, proliferation, and signaling. CD9 is ubiquitously expressed on the surface of various cell types, including platelets, leukocytes, epithelial cells, endothelial cells, and germ cells. It plays a critical role in cell-cell interactions, especially in the context of immune responses, reproduction, cancer metastasis, and viral infection.

One of the unique features of tetraspanins, including CD9, is their ability to organize membrane microdomains known as tetraspanin-enriched microdomains (TEMs). These microdomains function as platforms that regulate the spatial organization of other membrane proteins such as integrins, growth factor receptors, and co-receptors, thus modulating their signaling activity. CD9, in particular, interacts with several key molecules, including integrins (α6β1, α3β1), epidermal growth factor receptor (EGFR), and immunoglobulin superfamily proteins.

In addition to its involvement in normal cellular functions, CD9 has gained significant interest in cancer research, due to its role in tumor cell migration, invasion, and metastasis. It is often referred to as a metastasis suppressor due to its ability to reduce the metastatic potential of certain cancers. On the flip side, in other cancers, CD9 is overexpressed and may contribute to tumor progression, highlighting the complexity of its biological roles.

Protein Structure

CD9 is a 39-45 kDa protein composed of 228 amino acids and characterized by four transmembrane domains, which is typical of the tetraspanin family. Its structure can be divided into three main regions: the extracellular domains, transmembrane regions, and the cytoplasmic tail.

Primary Structure

CD9 contains the following key structural components:

• Four Transmembrane Domains (TM1-TM4): These domains consist of hydrophobic amino acid residues that allow the protein to span the plasma membrane four times. These regions are essential for maintaining the structure of the protein and its ability to interact with other membrane-bound molecules. The transmembrane helices of CD9 help in the oligomerization of CD9 and facilitate its interactions with other tetraspanins, contributing to the formation of TEMs.
• Two Extracellular Loops (EC1 and EC2): The small extracellular loop (EC1) is a short, N-terminal domain. The large extracellular loop (EC2) is a hallmark feature of tetraspanins, consisting of approximately 90 amino acids with several conserved cysteine residues that form disulfide bonds, giving structural stability to the molecule. The EC2 domain of CD9 is crucial for its interaction with other proteins such as integrins and EGFR.
• Cytoplasmic N- and C-Termini: Both termini are intracellular, relatively short, and contain phosphorylation sites that contribute to signal transduction upon ligand binding or upon interactions with other membrane receptors.

Tertiary and Quaternary Structure

The EC2 loop is the most functionally active region, mediating interactions with other membrane-bound proteins and forming multimeric complexes with other tetraspanins or non-tetraspanins. CD9 does not function alone but rather forms tetraspanin-enriched microdomains (TEMs), where it interacts with other tetraspanins, as well as integrins and growth factor receptors. These microdomains are dynamic and essential for proper functioning of the plasma membrane. TEMs organize protein-protein interactions that influence cellular processes such as adhesion and signal transduction.

CD9 is also known to form homodimers or heterodimers with other tetraspanins, which further modulates its ability to interact with external ligands. This multimerization is crucial for the functional versatility of CD9.

Classification and Subtypes

CD9 belongs to the tetraspanin family, also known as the TM4SF (transmembrane 4 superfamily). This family includes more than 30 members, which are distinguished by their four transmembrane regions and conserved cysteine residues in the large extracellular loop (EC2). CD9 shares many functional characteristics with other tetraspanins, particularly in terms of its ability to organize membrane complexes and regulate cell signaling.

There are no distinct subtypes of CD9, but isoforms generated through alternative splicing have been reported, although their functional significance is not fully understood. These isoforms may vary in their transmembrane domains or extracellular loops, potentially altering their interaction capabilities or signaling properties.

Function and Biological Significance

CD9 is a multifunctional protein involved in numerous physiological processes. Its primary functions include regulating cell adhesion, migration, fusion, and signaling. Through its interactions with integrins, EGFR, and other tetraspanins, CD9 exerts significant influence on cellular behavior.

Cell Adhesion and Migration

CD9 interacts with integrins (such as α6β1 and α3β1) to regulate cell adhesion to the extracellular matrix (ECM). It modulates integrin function, thereby influencing cell spreading, migration, and invasion. CD9's involvement in cell migration is particularly important in processes such as wound healing, immune responses, and angiogenesis. In cancer, CD9's role in cell migration becomes crucial, as its downregulation has been associated with increased metastatic potential in various cancers.

Cell Signaling

CD9 modulates various signaling pathways, particularly through its interaction with EGFR. By organizing EGFR within TEMs, CD9 can influence EGFR signaling, which is critical for processes such as cell proliferation, survival, and differentiation. CD9 also plays a role in the regulation of Wnt signaling, another pathway crucial for cell growth and development.

Role in Immune Function

CD9 is expressed on leukocytes, including monocytes, dendritic cells, and macrophages, where it modulates immune cell interactions and responses. It participates in phagocytosis, antigen presentation, and cytokine production. CD9 also influences B cell and T cell responses by regulating their interactions with other immune cells, and its role in immunological synapse formation is under investigation.

Role in Reproduction

CD9 plays a key role in sperm-egg fusion during fertilization. On the surface of oocytes, CD9 interacts with proteins on sperm cells to mediate their fusion, making it essential for fertility. CD9-null mice exhibit significant defects in egg-sperm fusion, further highlighting its critical function in reproduction.

Clinical Issues

CD9's involvement in cell adhesion and migration has significant implications for cancer progression, metastasis, and immune diseases. Its dual role in cancer—acting as both a metastasis suppressor in some contexts and as a promoter in others—makes it an intriguing target for research.

Cancer

CD9 expression has been shown to suppress metastasis in several cancers, including breast cancer, prostate cancer, melanoma, and colorectal cancer. In these cancers, higher levels of CD9 correlate with a reduced metastatic potential, and CD9 is considered a prognostic marker for cancer progression. On the other hand, CD9 overexpression has been linked to increased tumor growth in other cancers, such as acute myeloid leukemia (AML) and pancreatic cancer. Thus, CD9’s role in cancer is complex and appears to depend on the cellular and molecular context.

Immune-Related Disorders

CD9's involvement in immune cell signaling has potential implications in inflammatory diseases and autoimmune disorders. Aberrant CD9 expression or function could contribute to dysregulated immune responses, though further research is needed to elucidate its precise role in immune pathologies.

Reproductive Issues

Given CD9's role in sperm-egg fusion, its deficiency can lead to fertility issues. Women with reduced CD9 expression on their oocytes may face challenges with fertilization, and research into CD9-based therapies for infertility is ongoing.

Summary

CD9 is a crucial member of the tetraspanin family, involved in various cellular processes, including cell adhesion, migration, proliferation, and signal transduction. Its ability to organize membrane proteins into tetraspanin-enriched microdomains (TEMs) allows it to regulate interactions between key signaling molecules such as integrins and EGFR. Functionally, CD9 plays a significant role in immune responses, reproductive processes, and cancer biology.

The protein structure of CD9 is characterized by four transmembrane domains, two extracellular loops, and short intracellular tails, which are essential for its interactions with other proteins and its role in organizing membrane microdomains. Its role in cell adhesion and migration has implications in cancer progression, making it both a potential therapeutic target and a prognostic marker. Moreover, CD9 is essential for sperm-egg fusion, highlighting its role in fertility.

Given its wide-ranging functions, CD9 continues to be a molecule of great interest in immunology, cancer research, and reproductive biology. Understanding its structure and function could pave the way for novel therapeutic strategies in treating cancers, immune disorders, and infertility.