ITGA5 - integrin subunit alpha 5 |Elisa - Clia - Antibody - Protein

Background

Integrin subunit alpha 5 (ITGA5) is a critical component of the integrin family of transmembrane receptors, responsible for mediating interactions between cells and the extracellular matrix (ECM). ITGA5 pairs with integrin subunit beta 1 (ITGB1) to form the α5β1 integrin, also known as the fibronectin receptor. This integrin complex plays an essential role in cell adhesion, migration, proliferation, and survival by binding to fibronectin, an ECM glycoprotein. ITGA5-mediated interactions are important for various physiological processes, including embryonic development, wound healing, angiogenesis, and the regulation of cell differentiation. Dysregulation of ITGA5 has been implicated in several pathologies, such as fibrosis, cancer, and inflammatory diseases.

The ITGA5 gene is located on chromosome 12q13, encoding a large glycoprotein that is expressed in a wide range of tissues. ITGA5 is particularly abundant in fibroblasts, endothelial cells, and smooth muscle cells, where it participates in matrix assembly and tissue remodeling. Its upregulation has been observed in processes involving tissue repair and inflammation, and it is frequently overexpressed in cancer, making it a potential target for therapeutic interventions.

Protein Structure

ITGA5 is a type I transmembrane glycoprotein, characteristic of the alpha subunits in the integrin family. The structure of ITGA5 consists of approximately 1049 amino acids, divided into distinct regions, including the extracellular domain, transmembrane domain, and cytoplasmic domain.

Extracellular Domain:

• The extracellular domain of ITGA5 accounts for the majority of the protein and is responsible for binding to ligands in the ECM, particularly fibronectin. This domain can be further divided into several important regions:
• N-terminal β-propeller domain: Comprising seven blades, this region is responsible for binding to the RGD (Arg-Gly-Asp) motif found in fibronectin. The RGD binding site is crucial for the recognition and anchoring of cells to the ECM.
• Thigh and calf-1/calf-2 domains: These domains help maintain the integrin's structural integrity and contribute to ligand specificity. They also provide the structural flexibility required for integrin activation.
• Cation-binding sites: Divalent cations such as calcium (Ca²⁺) and magnesium (Mg²⁺) are essential for integrin-ligand interactions and activation. These ions are involved in stabilizing the active conformation of the integrin, facilitating high-affinity binding to ECM proteins.

Transmembrane Domain:

• The transmembrane domain of ITGA5 consists of a single alpha helix that spans the plasma membrane. This region is critical for heterodimerization with the beta subunit (ITGB1). The transmembrane domain also participates in the transmission of signals from the extracellular environment to the intracellular machinery, a process known as outside-in signaling.

Cytoplasmic Domain:

• The cytoplasmic domain of ITGA5 is relatively short but plays a pivotal role in integrin activation and intracellular signaling. It contains specific motifs that interact with proteins such as talin, kindlin, and paxillin, which link the integrin to the actin cytoskeleton. The cytoplasmic domain regulates inside-out signaling, which controls the integrin’s affinity for its ligands by altering the conformation of the extracellular domain.
• Phosphorylation and dephosphorylation of residues in the cytoplasmic tail regulate the activation state of the integrin, modulating its ability to participate in cell adhesion, migration, and signal transduction.

Heterodimerization:

• ITGA5 forms a functional receptor only when paired with ITGB1, resulting in the α5β1 integrin. This heterodimer is necessary for binding fibronectin in the ECM and mediating integrin signaling. Heterodimerization is a critical step in integrin function because neither subunit alone is capable of high-affinity ligand binding.

Classification and Subtypes

Integrins are categorized based on their alpha and beta subunit pairings, which determine their ligand specificity and biological functions. ITGA5 is classified as an alpha integrin subunit and pairs exclusively with ITGB1 to form the α5β1 integrin, also known as the fibronectin receptor.

• α5β1 integrin: The primary ligand for this integrin is fibronectin, which contains an RGD motif recognized by the α5β1 integrin. This receptor plays a critical role in cell adhesion to the ECM, migration, and matrix assembly. It is also involved in signal transduction pathways that regulate cell survival and proliferation.

Function and Biological Significance

The α5β1 integrin formed by ITGA5 and ITGB1 mediates several key biological processes, including:

Cell Adhesion and Migration:

• ITGA5 is a major mediator of cell-ECM adhesion by binding to fibronectin in the ECM. This interaction is essential for cell migration during processes such as wound healing, angiogenesis, and tissue remodeling. The α5β1 integrin allows cells to attach to the fibronectin-rich matrix and move in response to external stimuli.

Matrix Assembly and Remodeling:

• ITGA5 is essential for the assembly of fibronectin fibrils in the ECM, a process critical for maintaining tissue architecture and function. The α5β1 integrin facilitates the polymerization of fibronectin into a fibrillar network, which in turn regulates ECM stiffness and tissue organization.
• This process is particularly important during tissue repair, where cells need to remodel the ECM to restore normal function. In pathological conditions such as fibrosis, excessive fibronectin matrix deposition can lead to tissue scarring and dysfunction.

Cell Signaling and Survival:

• Through outside-in signaling, ITGA5 can transmit mechanical and chemical signals from the ECM into the cell, influencing various intracellular signaling pathways. For instance, ITGA5 activates pathways such as the focal adhesion kinase (FAK) and phosphoinositide 3-kinase (PI3K) pathways, which promote cell survival, proliferation, and migration.
• This signaling also helps cells sense the biochemical composition and mechanical properties of their environment, allowing them to adapt their behavior accordingly.

Developmental Roles:

• ITGA5 is crucial for embryonic development, particularly in processes such as vascular formation and organogenesis. Mice lacking ITGA5 exhibit defects in the development of the cardiovascular system and mesoderm, underscoring its role in normal embryonic morphogenesis.

Cancer Progression:

• ITGA5 has been implicated in tumor progression and metastasis. In many cancers, including breast, prostate, and lung cancers, ITGA5 expression is upregulated, promoting tumor cell adhesion, invasion, and survival. The α5β1 integrin facilitates the attachment of cancer cells to the ECM, enabling them to invade surrounding tissues and establish secondary tumors at distant sites.

Clinical Issues

Cancer:

• Overexpression of ITGA5 is associated with tumor progression, metastasis, and resistance to therapy in various cancers. The α5β1 integrin promotes cancer cell adhesion to the ECM and migration, facilitating invasion and metastasis. Targeting α5β1 integrin in cancer therapy is being explored as a strategy to inhibit tumor progression and metastasis.
• Monoclonal antibodies and small molecule inhibitors designed to block the interaction between α5β1 integrin and fibronectin are under investigation for their potential to reduce tumor cell adhesion and metastasis.

Fibrosis:

• Excessive ITGA5 activity has been linked to fibrotic diseases, where abnormal deposition of fibronectin and other ECM components leads to tissue scarring. In diseases like pulmonary fibrosis and liver fibrosis, ITGA5-mediated fibronectin matrix assembly contributes to the pathological accumulation of ECM, impairing normal tissue function.
• Therapeutic strategies aimed at inhibiting ITGA5 activity could potentially alleviate fibrosis by reducing ECM deposition and remodeling.

Inflammatory Diseases:

• In conditions such as rheumatoid arthritis and inflammatory bowel disease (IBD), ITGA5 is involved in the migration of inflammatory cells to affected tissues. By mediating immune cell adhesion to the ECM, ITGA5 contributes to the inflammatory response in these diseases.
• Blocking α5β1 integrin could be a therapeutic approach to reduce inflammation and tissue damage in chronic inflammatory conditions.

Summary

ITGA5, a subunit of the α5β1 integrin, plays a critical role in cell-ECM adhesion, migration, matrix assembly, and cell signaling. The extracellular domain of ITGA5 binds to fibronectin, while its transmembrane and cytoplasmic domains facilitate dimerization with ITGB1 and intracellular signaling. Through its interactions with fibronectin, ITGA5 is involved in essential biological processes such as wound healing, angiogenesis, and tumor progression. Dysregulation of ITGA5 is implicated in diseases such as cancer, fibrosis, and inflammatory diseases, making it a potential target for therapeutic intervention.