ITGA3 - integrin subunit alpha 3 |Elisa - Clia - Antibody - Protein

Background

Integrin subunit alpha 3 (ITGA3) is part of the integrin family, which are heterodimeric transmembrane receptors crucial for mediating interactions between cells and the extracellular matrix (ECM). Integrins are essential for cell adhesion, migration, and signal transduction, contributing to various biological processes such as tissue repair, immune response, and embryonic development. ITGA3 pairs with integrin beta 1 (ITGB1) to form the α3β1 integrin, which serves as a receptor for laminin, fibronectin, and other ECM components, playing a vital role in cell adhesion and migration.

ITGA3 is encoded by the ITGA3 gene, located on chromosome 17q21.33. The expression of ITGA3 is widespread, particularly in tissues such as epithelial cells, endothelial cells, and neurons. The α3β1 integrin is involved in important physiological processes like embryogenesis, angiogenesis, and wound healing, as well as in tumor metastasis and invasion in pathological conditions. In cancer biology, ITGA3 is often associated with tumor progression and can influence cellular invasiveness.

Protein Structure

The ITGA3 protein is a type I transmembrane glycoprotein consisting of approximately 1051 amino acids. Similar to other integrins, ITGA3 has three distinct domains:

Extracellular Domain:

• The extracellular domain is the largest portion of ITGA3, consisting of about 950 amino acids. It is responsible for binding ECM components, such as laminin, collagen, and fibronectin. The extracellular structure is highly conserved among integrins and includes:
• I-domain (Insert domain): A domain that enables specific ligand binding, with a preference for laminin. This region is critical for interaction with ECM proteins and requires divalent cations (e.g., Mg²⁺, Ca²⁺, and Mn²⁺) for structural stability and ligand binding.
• Seven-bladed β-propeller domain: This domain plays a pivotal role in recognizing and binding ECM proteins. It forms part of the headpiece of the integrin, involved in the specificity of ECM interactions.
• Thigh and Calf-1/2 Domains: These domains are involved in stabilizing the integrin structure and facilitating conformational changes necessary for integrin activation.
• Cation-binding sites: These sites in the extracellular domain regulate the integrin's affinity for ligands by coordinating with divalent cations, which are necessary for receptor activation.

Transmembrane Domain:

• The transmembrane domain of ITGA3 consists of a single-pass alpha-helical segment of around 20-25 hydrophobic amino acids. This region is critical for dimerization with ITGB1, forming the functional α3β1 integrin receptor. The transmembrane domain also participates in the regulation of integrin activation and stabilizes the inactive conformation of the integrin dimer when not bound to a ligand.

Cytoplasmic Domain:

• The cytoplasmic tail of ITGA3 is relatively short, containing approximately 50-70 amino acids. Despite its size, this domain plays a crucial role in integrin signaling by interacting with intracellular signaling molecules and cytoskeletal proteins such as talin, paxillin, and kindlin.
• Inside-out signaling: The cytoplasmic domain is involved in regulating integrin activation via inside-out signaling pathways. These pathways modulate the integrin's ability to switch between an inactive (bent) and an active (extended) conformation, which affects ligand binding.
• Outside-in signaling: Once integrins bind to ECM components, the cytoplasmic domain transduces signals into the cell, influencing processes such as cell survival, migration, proliferation, and cytoskeletal rearrangement. Phosphorylation of specific residues within the cytoplasmic domain can modulate these interactions.

Heterodimerization:

• ITGA3 forms a non-covalent heterodimer with integrin beta 1 (ITGB1) to create the α3β1 integrin. This dimerization occurs through the interaction of both subunits' extracellular, transmembrane, and cytoplasmic regions. The combination of the two subunits confers the specificity of the receptor, enabling α3β1 integrin to interact with laminin and fibronectin in the ECM.

Classification and Subtypes

Integrins are classified based on their subunit composition and the ligands they bind. ITGA3 belongs to the integrin alpha subunit family, which includes various alpha subunits that dimerize with specific beta subunits to form functional integrin receptors. α3β1 integrin is primarily classified as a laminin receptor, but it can also bind to other ECM proteins, including fibronectin and collagen.

In the broader integrin classification, α3β1 integrin is grouped with other integrins that participate in cell-matrix adhesion and cell migration. While ITGA3 does not have distinct isoforms, alternative splicing can occur, leading to variations in the cytoplasmic domain that may influence its interaction with intracellular signaling proteins. These splice variants can result in functional differences in various tissues or cellular contexts.

Function and Biological Significance

The primary function of ITGA3 is to mediate cell adhesion to the ECM and contribute to processes such as cell migration, cell proliferation, and tissue morphogenesis. The α3β1 integrin plays a particularly critical role in tissues where laminin is a dominant component of the basement membrane, such as the skin, kidney, and brain.

Cell Adhesion and Migration:

• ITGA3 plays a pivotal role in adhesion to ECM components such as laminin and fibronectin. This adhesion is crucial for maintaining tissue structure and facilitating cell migration during processes like wound healing and development. The α3β1 integrin is essential for keratinocyte migration during wound closure and epithelial cell movement in tissue repair.
• In the nervous system, ITGA3 is expressed in neurons and glial cells, where it contributes to axon guidance, neural migration, and synapse formation.

Signal Transduction:

• Through outside-in signaling, ITGA3 activates pathways that influence cell survival, proliferation, and differentiation. It does so by recruiting and interacting with intracellular signaling proteins like focal adhesion kinase (FAK), Src family kinases, and Rho GTPases, which regulate cytoskeletal dynamics and cell movement.
• ITGA3 also participates in inside-out signaling, whereby intracellular signals (e.g., via talin or kindlin) modulate the integrin’s ability to bind ligands, adjusting cell adhesion properties in response to environmental cues.

Developmental Roles:

• During embryogenesis, ITGA3 is crucial for the development of the basement membrane and the formation of epithelial structures. For example, in kidney development, ITGA3 mediates interactions between epithelial cells and the basement membrane, which is critical for the formation of nephron structures.

Tumor Biology:

• ITGA3 has been implicated in tumor progression and metastasis. In various cancers, including melanoma, breast cancer, and lung cancer, upregulation of ITGA3 enhances tumor cell adhesion to ECM components, promoting invasion and metastasis. By facilitating cell migration and ECM interaction, ITGA3 enables tumor cells to invade surrounding tissues and establish metastatic sites.
• Interestingly, ITGA3’s role in cancer can be context-dependent. In some cancer types, downregulation of ITGA3 correlates with increased tumor invasiveness, indicating a complex role in tumor biology.

Clinical Issues

Cancer:

• ITGA3 is often overexpressed in various types of cancers, including breast cancer, non-small cell lung cancer, and melanoma. Elevated ITGA3 levels are associated with enhanced cell migration, invasion, and poor prognosis in these cancers. Targeting ITGA3-mediated pathways has been proposed as a therapeutic strategy to reduce metastasis and inhibit tumor progression.

Epidermolysis Bullosa:

• Mutations in ITGA3 are associated with epidermolysis bullosa, a rare genetic disorder characterized by skin fragility and blistering. This condition arises from defective adhesion between epithelial cells and the basement membrane due to dysfunctional α3β1 integrin.

Kidney Disease:

• Deficiencies in ITGA3 expression or function can lead to glomerular diseases such as glomerulopathy or nephrotic syndrome. The α3β1 integrin is crucial for maintaining the integrity of the glomerular basement membrane in the kidney, and its dysfunction can lead to proteinuria and renal failure.

Summary

Integrin subunit alpha 3 (ITGA3) is a key component of the α3β1 integrin, a receptor essential for cell adhesion, migration, and signaling. Structurally, ITGA3 contains an extracellular domain for ligand binding, a transmembrane domain for dimerization, and a cytoplasmic domain for intracellular signaling. ITGA3 plays important roles in tissue development, wound healing, and tumor metastasis, while dysregulation of ITGA3 has been implicated in cancer progression, epidermolysis bullosa, and renal diseases. Understanding ITGA3’s structure and function provides critical insights into its role in both health and disease.