ITGA2 - integrin subunit alpha 2 |Elisa - Clia - Antibody - Protein

Background

Integrin subunit alpha 2 (ITGA2) is part of the integrin family, a group of heterodimeric transmembrane receptors composed of alpha and beta subunits. These receptors are critical for cell-ECM (extracellular matrix) interactions and cell-cell adhesion, with a wide variety of biological processes such as cell migration, proliferation, differentiation, and signal transduction. ITGA2 forms a dimer with integrin beta 1 (ITGB1), giving rise to the α2β1 integrin, also known as the collagen receptor. This receptor specifically binds to collagen and laminin in the ECM, playing a crucial role in mediating cellular adhesion to collagen fibers in tissues.

The ITGA2 gene, located on chromosome 5q11.2, encodes the alpha 2 integrin subunit. ITGA2 is expressed in various cell types, including epithelial cells, platelets, fibroblasts, and immune cells. Its activity is essential in processes such as wound healing, angiogenesis, hemostasis, and the maintenance of tissue integrity. Additionally, α2β1 integrin has significant involvement in tumor biology, where it modulates cancer cell invasion and metastasis by interacting with the ECM.

Protein Structure

The ITGA2 protein is a type I transmembrane glycoprotein, consisting of approximately 1170 amino acids, and like other integrins, it has a structure divided into extracellular, transmembrane, and cytoplasmic domains:

Extracellular Domain:

• The extracellular portion of ITGA2 constitutes the largest part of the protein, about 1000 amino acids in length. This domain is responsible for ligand binding, specifically collagen types I and IV, and laminin. The extracellular domain contains several key structural motifs:
• I-domain (Insert domain or von Willebrand factor type A domain): The I-domain is crucial for collagen binding and is stabilized by divalent cations, such as Mg²⁺ or Mn²⁺, which enhance the receptor's affinity for its ligand.
• Seven-bladed β-propeller: This structure is essential for the interaction with collagen and is a hallmark of the integrin alpha subunit family.
• Calcium-binding motifs: The extracellular domain has several Ca²⁺ binding sites, which regulate the conformational changes necessary for ligand binding and the integrin’s activation state.
• The I-domain in ITGA2 undergoes conformational changes that mediate its binding to ECM components like collagen. Ligand binding leads to activation and outside-in signaling, where integrins relay signals from the ECM into the cell.

Transmembrane Domain:

• The transmembrane region is a single alpha-helix spanning the lipid bilayer, composed of about 20-25 hydrophobic amino acids. It plays a crucial role in the heterodimerization with the beta subunit (ITGB1), ensuring proper integrin function. The interaction between the transmembrane domains of both alpha and beta subunits is essential for maintaining the integrin in its inactive, bent conformation when not engaged with ligands.

Cytoplasmic Domain:

• The cytoplasmic tail of ITGA2 is relatively short, consisting of around 50 amino acids. Despite its size, the cytoplasmic domain plays a significant role in inside-out signaling, which regulates integrin activation, and outside-in signaling, which transduces signals from the ECM into intracellular responses. Key interactions with cytoplasmic proteins like talin, kindlin, and paxillin link the integrin to the actin cytoskeleton, modulating cell motility, shape, and survival.
• Additionally, phosphorylation of certain residues in the cytoplasmic domain can modulate the integrin’s interaction with intracellular signaling proteins, affecting cellular responses to environmental changes.

Heterodimerization:

• ITGA2 forms a heterodimer with integrin beta 1 (ITGB1) to create the α2β1 integrin receptor. This dimerization occurs through non-covalent interactions between the extracellular, transmembrane, and cytoplasmic domains of the two subunits. The α2β1 integrin primarily functions as a collagen receptor, but it also binds to laminins and other ECM proteins in specific cellular contexts.

Classification and Subtypes

ITGA2 belongs to the broader integrin family, which consists of 24 unique heterodimers formed by combinations of 18 alpha and 8 beta subunits. Integrins are classified based on their ligand-binding specificity and cellular functions. The α2β1 integrin, specifically, is classified as a collagen receptor integrin. Its primary ligand is collagen, but it also recognizes laminin and fibronectin under certain conditions.

Unlike other integrins, ITGA2 does not have distinct isoforms or subtypes. However, its function and activity can vary based on the cell type it is expressed in, and the environmental cues it responds to.

Function and Biological Significance

ITGA2, in association with ITGB1, forms the α2β1 integrin, which plays a fundamental role in regulating cell-ECM interactions. Key functions of ITGA2 include:

Cell Adhesion and Migration:

• As a collagen receptor, α2β1 integrin mediates the adhesion of cells to collagenous matrices, which is critical for maintaining tissue integrity and structure. It is highly expressed in cells that interact with collagen-rich environments, such as epithelial cells, fibroblasts, and platelets.
• During cell migration, ITGA2 is involved in the dynamic interaction between cells and the ECM. This process is essential for tissue remodeling, angiogenesis, and immune responses.

Wound Healing and Tissue Repair:

• ITGA2 is highly expressed in cells involved in wound healing. It plays a pivotal role in fibroblast adhesion to the ECM, promoting their migration and activation during the wound healing process. The receptor facilitates the remodeling of the ECM, aiding in the repair of damaged tissues.
• In endothelial cells, ITGA2 is involved in angiogenesis, where it helps guide the formation of new blood vessels, particularly in collagen-rich environments.

Hemostasis and Platelet Function:

• ITGA2 is expressed on platelets and is crucial for their adhesion to exposed collagen at sites of vascular injury, contributing to thrombus formation. The α2β1 integrin, in conjunction with other integrins such as αIIbβ3, facilitates stable platelet adhesion, aggregation, and the initiation of the clotting cascade.
• Defects in α2β1 integrin can lead to impaired platelet function, potentially resulting in bleeding disorders.

Signal Transduction:

• ITGA2 integrins mediate bidirectional signaling across the cell membrane, transmitting signals from the ECM to the cell (outside-in signaling) and regulating integrin activity from inside the cell (inside-out signaling). Through these pathways, ITGA2 influences cell survival, proliferation, and differentiation.
• The receptor is linked to intracellular signaling molecules such as focal adhesion kinase (FAK), Src family kinases, and Rho GTPases, which regulate cell movement, cytoskeletal dynamics, and cell cycle progression.

Tumor Biology:

• ITGA2 is implicated in tumor progression and metastasis. High expression of ITGA2 has been observed in various cancers, including breast cancer, prostate cancer, and gastric cancer. The ability of ITGA2 to mediate tumor cell adhesion to collagen-rich ECM can enhance invasion and metastasis. Moreover, ITGA2 signaling may contribute to tumor cell survival and resistance to chemotherapy.
• Conversely, in some contexts, ITGA2 can act as a tumor suppressor, particularly in cases where it inhibits the migration and invasion of certain cancer cells. This dual role highlights the complexity of ITGA2 in cancer biology, depending on the tumor type and microenvironment.

Clinical Issues

Cancer:

• ITGA2 plays a critical role in cancer cell-ECM interactions, influencing tumor invasion, angiogenesis, and metastasis. Increased expression of ITGA2 in some cancers has been associated with a more aggressive phenotype and poor prognosis. Conversely, in certain cancers, loss of ITGA2 expression can enhance invasiveness, indicating that its role is context-dependent.
• As a result, ITGA2 is considered a potential therapeutic target in cancer, with strategies aimed at blocking its interaction with collagen or inhibiting its signaling pathways.

Hemorrhagic Disorders:

• ITGA2 is essential for platelet adhesion to collagen during the formation of a hemostatic plug. Mutations or deficiencies in ITGA2 can lead to bleeding disorders, such as Glanzmann thrombasthenia, characterized by impaired platelet function and excessive bleeding.

Fibrotic Diseases:

• Dysregulated ITGA2 expression has been implicated in fibrosis, a pathological condition characterized by excessive ECM deposition and tissue stiffening. In diseases such as pulmonary fibrosis and liver cirrhosis, ITGA2-mediated interactions with collagen may exacerbate the fibrotic process by promoting fibroblast activation and ECM remodeling.

Autoimmune Diseases:

• ITGA2 has also been linked to autoimmune diseases, where aberrant immune cell-ECM interactions contribute to tissue inflammation and damage. In particular, ITGA2 may play a role in conditions such as rheumatoid arthritis and systemic sclerosis, where immune cells invade and remodel collagen-rich tissues.

Summary

Integrin subunit alpha 2 (ITGA2) is a key player in cell-ECM interactions, primarily through its formation of the α2β1 integrin heterodimer. This collagen-binding integrin mediates critical processes such as cell adhesion, migration, wound healing, angiogenesis, platelet function, and tumor progression. ITGA2's structure consists of a large extracellular domain for ligand binding, a transmembrane region for dimerization, and a cytoplasmic domain for signaling interactions. Dysregulation of ITGA2 is associated with a variety of pathological conditions, including cancer, fibrosis, autoimmune diseases, and bleeding disorders, making it a significant focus for therapeutic research. Understanding its structure and functions provides crucial insights into its role in both normal physiology and disease progression.