ITGA6 - integrin subunit alpha 6 |Elisa - Clia - Antibody - Protein

Background

Integrin subunit alpha 6 (ITGA6) is part of the integrin family, a group of transmembrane receptors that mediate cell adhesion and interactions with the extracellular matrix (ECM). ITGA6 specifically pairs with either integrin beta 1 (ITGB1) or integrin beta 4 (ITGB4) to form the α6β1 and α6β4 integrins, which primarily bind to laminins, an essential component of the basement membrane. These integrin complexes play critical roles in tissue integrity, cellular architecture, and signal transduction, mediating functions such as cell adhesion, migration, proliferation, and differentiation.

The ITGA6 gene is located on chromosome 2q31.1 and encodes a protein that is widely expressed in various tissues, including epithelial cells, endothelial cells, and stem cells. ITGA6 is particularly important in tissues that depend on strong adhesion to the basement membrane, such as the skin, intestines, and kidneys. ITGA6 also plays a significant role during embryonic development, where it contributes to the formation and stabilization of epithelial layers and tissues.

In pathological conditions, dysregulation of ITGA6 has been implicated in cancer progression, tissue fibrosis, and inflammatory diseases. Due to its involvement in cancer cell migration and invasion, ITGA6 is considered a potential therapeutic target, particularly in cancers of epithelial origin.

Protein Structure

ITGA6 is a type I transmembrane glycoprotein that consists of approximately 1,140 amino acids and has the characteristic structure of an integrin alpha subunit. Its structure is divided into three major regions: the extracellular domain, transmembrane domain, and cytoplasmic domain.

Extracellular Domain:

The extracellular domain of ITGA6 is responsible for ligand binding, specifically to laminins in the ECM. This domain can be subdivided into several important regions:

• N-terminal β-propeller domain: Composed of seven blades arranged in a propeller-like configuration, this domain facilitates the recognition and binding of laminin. Laminin recognition occurs through specific sites within the β-propeller domain that bind to sequences in laminins, particularly the LG (laminin G-like) domain.
• Thigh and calf-1/calf-2 domains: These domains provide structural support and maintain the integrin's flexibility. The thigh domain is essential for integrin activation and plays a role in conformational changes that occur during ligand binding and integrin activation.
• Cation-binding sites: Like other integrins, ITGA6 requires divalent cations such as calcium (Ca²⁺) and magnesium (Mg²⁺) for proper ligand binding and integrin activation. These cations stabilize the ligand-binding sites and contribute to the structural integrity of the integrin.

Transmembrane Domain:

• The transmembrane domain of ITGA6 is a single-pass alpha helix that anchors the integrin to the cell membrane. This domain is involved in the interaction with the beta subunit (ITGB1 or ITGB4) and plays a critical role in the transmission of signals across the membrane, a process known as outside-in signaling. Additionally, the transmembrane domain participates in heterodimerization, which is essential for integrin function.

Cytoplasmic Domain:

• The cytoplasmic domain of ITGA6 is relatively short but highly important for intracellular signaling and interaction with the cytoskeleton. It contains specific motifs that interact with cytoskeletal proteins such as talin, paxillin, and kindlin, linking the integrin to the actin cytoskeleton.
• The cytoplasmic domain also regulates inside-out signaling, which modulates the activation state of the integrin and its affinity for ligands. Phosphorylation and other post-translational modifications of the cytoplasmic tail play a crucial role in the dynamic regulation of integrin activity, particularly in response to cellular signals.

Classification and Subtypes

Integrins are classified based on their alpha and beta subunit pairings, which determine their ligand specificity and functional roles. ITGA6 forms two major heterodimers with beta subunits, each with distinct biological functions and tissue distributions:

α6β1 Integrin:

• This heterodimer binds to laminin isoforms in the basement membrane and is widely expressed in various tissues, including the skin, kidneys, and intestines. The α6β1 integrin is essential for cell adhesion, migration, and survival, particularly in epithelial and endothelial cells. It is also involved in stem cell maintenance and wound healing.

α6β4 Integrin:

• The α6β4 integrin is uniquely associated with hemidesmosomes, specialized structures that anchor epithelial cells to the basement membrane. This integrin is expressed primarily in stratified epithelial tissues, such as the skin, where it maintains tissue integrity and supports mechanical strength. It plays a crucial role in the adhesion of keratinocytes to the basement membrane and is essential for the structural stability of the epidermis.

Function and Biological Significance

ITGA6, through its heterodimers α6β1 and α6β4, performs essential biological functions related to cell adhesion, migration, and signaling:

Cell Adhesion:

• ITGA6, particularly in the α6β1 form, facilitates cell adhesion to the basement membrane by binding to laminin. This interaction is crucial for maintaining the structural integrity of epithelial layers and ensuring proper cell positioning and tissue architecture.

Tissue Integrity and Hemidesmosomes:

• In the α6β4 form, ITGA6 is a key component of hemidesmosomes, anchoring epithelial cells to the basement membrane. This integrin plays a fundamental role in maintaining tissue stability, particularly in high-stress tissues like the skin. Mutations or dysfunction in α6β4 can lead to disorders such as epidermolysis bullosa, a condition characterized by fragile skin that easily blisters due to poor cell-matrix adhesion.

Cell Migration and Wound Healing:

• ITGA6 promotes cell migration during wound healing and tissue repair. The α6β1 integrin facilitates the movement of epithelial cells to sites of injury by binding to laminin and regulating cytoskeletal dynamics. ITGA6’s role in cell migration is also critical during embryonic development, particularly in the formation of epithelial tissues and organs.

Signal Transduction:

• ITGA6 participates in signal transduction processes that regulate cellular responses to changes in the ECM. Upon binding to laminin, ITGA6 triggers outside-in signaling pathways that influence cell survival, differentiation, and proliferation. For example, ITGA6 activates the PI3K-Akt pathway, promoting cell survival and growth.
• Inside-out signaling modulates ITGA6’s binding affinity to laminin, allowing cells to dynamically adjust their adhesion properties in response to environmental cues. This is important for processes like tissue remodeling and cell migration.

Stem Cell Maintenance:

• ITGA6 is a marker for stem cells, particularly in epithelial tissues such as the skin and intestines. It is involved in maintaining the stem cell niche, ensuring that stem cells remain anchored to their niche in the basement membrane, which is essential for tissue homeostasis and regeneration.

Clinical Issues

Cancer:

• ITGA6 has been implicated in cancer progression, particularly in epithelial cancers such as breast, prostate, and lung cancers. Overexpression of ITGA6, especially in its α6β1 and α6β4 forms, is associated with increased tumor cell adhesion to the ECM, enhanced migration, and invasion.
• The α6β4 integrin has been linked to cancer metastasis and poor prognosis in several cancers. It promotes tumor cell survival and resistance to apoptosis by activating signaling pathways such as PI3K-Akt and Rac1. This integrin is also involved in the epithelial-to-mesenchymal transition (EMT), a process that enhances tumor cell invasiveness and dissemination.

Epidermolysis Bullosa:

• Mutations in ITGA6 or ITGB4 cause junctional epidermolysis bullosa, a genetic disorder characterized by skin fragility and blistering. This condition results from defective hemidesmosomes, which fail to anchor epithelial cells properly to the basement membrane. Patients with this disorder experience severe skin blistering and complications such as infections and scarring.

Fibrosis:

• ITGA6 is involved in tissue fibrosis, a pathological process characterized by excessive ECM deposition and scar formation. In diseases such as pulmonary fibrosis and liver fibrosis, ITGA6-mediated interactions with laminin contribute to the abnormal accumulation of ECM components, leading to tissue stiffness and impaired organ function.

Inflammatory Diseases:

• Dysregulation of ITGA6 has been implicated in chronic inflammatory diseases such as inflammatory bowel disease (IBD) and psoriasis. In these conditions, altered integrin expression and function contribute to abnormal cell adhesion, migration, and immune cell activation, exacerbating tissue inflammation and damage.

Summary

Integrin subunit alpha 6 (ITGA6) plays a pivotal role in cell adhesion, migration, and signal transduction, primarily through its interactions with laminins in the basement membrane. ITGA6 forms heterodimers with ITGB1 and ITGB4, which are critical for tissue integrity, particularly in epithelial layers. ITGA6 also participates in wound healing, stem cell maintenance, and cancer progression. Dysregulation of ITGA6 is associated with diseases such as cancer, fibrosis, epidermolysis bullosa, and inflammatory disorders, highlighting its significance in both normal physiology and pathological conditions.