ITGAV - integrin subunit alpha V |Elisa - Clia - Antibody - Protein

Background

Integrin subunit alpha V (ITGAV) is a crucial component of the integrin family, a group of transmembrane receptors involved in cell-cell and cell-extracellular matrix (ECM) interactions. Integrins are heterodimeric proteins composed of alpha (α) and beta (β) subunits that, when combined, form receptors with various functions, primarily in cell adhesion, migration, proliferation, and signal transduction. ITGAV plays a particularly important role in binding to multiple ligands, including vitronectin, fibronectin, osteopontin, and components of the ECM, enabling it to mediate diverse biological processes such as angiogenesis, tissue repair, immune responses, and tumorigenesis.

The gene encoding integrin alpha V (ITGAV) is located on chromosome 2q31.1 in humans. ITGAV pairs with several beta subunits (particularly β1, β3, β5, β6, and β8) to form distinct integrin heterodimers, each with unique ligand specificity and biological function. The most well-characterized integrins involving ITGAV are αvβ3, αvβ5, αvβ6, and αvβ8, which play significant roles in processes like wound healing, angiogenesis, and tumor progression.

Protein Structure

ITGAV is a transmembrane glycoprotein with a highly specialized structure, consisting of extracellular, transmembrane, and cytoplasmic domains. Its structure allows for dynamic changes in conformation between inactive (bent) and active (extended) states, depending on the cellular environment and ligand interactions.

Extracellular Domain:

• The extracellular portion of ITGAV is the largest region, comprising ~1000 amino acids. It is responsible for binding to ligands and facilitating cell-ECM interactions.
• ITGAV contains seven FG-GAP repeats, which fold into a beta-propeller structure at its N-terminal region. This beta-propeller domain is essential for recognizing and binding to ligands that contain RGD motifs (arginine-glycine-aspartic acid), such as vitronectin and fibronectin.
• The I-like domain of ITGAV, located adjacent to the β-propeller, also plays a role in ligand binding and is involved in the allosteric regulation of integrin activation.
• ITGAV forms an alpha-beta heterodimer through non-covalent interactions with the β subunits. Upon ligand binding, the integrin undergoes a conformational change that shifts it from a low-affinity, inactive state to a high-affinity, extended, and active conformation. This structural flexibility is key to its function in cell adhesion and signaling.

Transmembrane Domain:

• The transmembrane region of ITGAV consists of a single alpha-helical domain that spans the lipid bilayer. This region anchors the protein to the cell membrane and is involved in transmitting signals from the extracellular matrix into the intracellular environment (a process known as "outside-in" signaling).
• The interaction between the transmembrane domains of the α and β subunits is critical for maintaining the inactive state of the integrin. Separation of these domains is one of the first steps in integrin activation.

Cytoplasmic Domain:

• The cytoplasmic tail of ITGAV is relatively short but plays a crucial role in signal transduction. It interacts with cytoplasmic proteins such as talin, kindlin, and paxillin, which help regulate integrin activation and link the integrin to the actin cytoskeleton.
• Through these interactions, ITGAV influences cellular processes such as migration, spreading, and the assembly of focal adhesions, key for cellular responses to mechanical signals from the ECM.
• The cytoplasmic tail is also important for inside-out signaling, where intracellular signals lead to changes in the integrin's affinity for extracellular ligands, allowing dynamic regulation of cell adhesion.

Classification and Subtypes

ITGAV pairs with various beta subunits to form functional integrins. The specific heterodimer formed by ITGAV determines its ligand-binding properties and biological functions. Some key heterodimers include:

1. αvβ3: This integrin binds to vitronectin, fibronectin, and other RGD-containing ligands. It plays a significant role in angiogenesis, bone resorption, and tumor metastasis.
2. αvβ5: Involved in phagocytosis and tumor progression, αvβ5 interacts primarily with vitronectin and is crucial for the uptake of apoptotic cells.
3. αvβ6: This integrin is primarily expressed on epithelial cells and binds to ligands like fibronectin and latent TGF-β1. It has been implicated in tissue repair, fibrosis, and cancer.
4. αvβ8: This integrin regulates TGF-β activation and is involved in brain development and immune regulation. Dysregulation of αvβ8 is associated with cerebral cavernous malformations and cancer.
5. αvβ1: Although less well characterized, αvβ1 has been implicated in fibronectin binding and cell migration.

Each of these integrin heterodimers contributes to various biological processes, such as immune responses, wound healing, inflammation, and tumor progression.

Function and Biological Significance

ITGAV plays a multifaceted role in cell adhesion, migration, and signaling, largely due to its ability to bind a variety of ECM proteins through its interaction with different β subunits. The primary functions of ITGAV include:

Cell Adhesion and Migration:

• ITGAV mediates the adhesion of cells to ECM components like vitronectin and fibronectin, which is essential for processes such as wound healing, angiogenesis, and tissue repair.
• It also facilitates cell migration by forming focal adhesions, linking the ECM to the actin cytoskeleton, and enabling cells to respond to mechanical and chemical signals from their environment. These processes are essential in development, tissue regeneration, and immune responses.

Angiogenesis:

• ITGAV, particularly through its interaction with β3 and β5 subunits, plays a pivotal role in angiogenesis, the formation of new blood vessels. This is especially important in tumor growth and wound healing, where new blood vessel formation is required to supply oxygen and nutrients.
• The integrins αvβ3 and αvβ5 are expressed on endothelial cells and promote angiogenesis by interacting with growth factors like VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor), aiding in endothelial cell migration and survival.

Tumor Progression and Metastasis:

• ITGAV is frequently upregulated in various cancers and is associated with tumor progression and metastasis. By promoting cell migration, angiogenesis, and invasion, ITGAV integrins, especially αvβ3 and αvβ5, contribute to the ability of cancer cells to invade surrounding tissues and establish metastases at distant sites.
• Additionally, ITGAV can interact with proteolytic enzymes, such as matrix metalloproteinases (MMPs), to degrade the ECM, further facilitating tumor invasion and metastasis.

TGF-β Activation:

• Integrins like αvβ6 and αvβ8 are involved in the activation of TGF-β, a critical cytokine for regulating immune responses, wound healing, and fibrosis. Dysregulation of TGF-β activation via ITGAV integrins can lead to fibrotic diseases and contribute to the immune escape mechanisms of tumors.

Immune Modulation:

• ITGAV plays a role in immune regulation by mediating phagocytosis and TGF-β activation. In particular, αvβ5 is involved in the clearance of apoptotic cells (efferocytosis), a process important for preventing inflammation and maintaining immune homeostasis.

Clinical Issues

The dysregulation of ITGAV integrins has been implicated in various diseases, including cancer, fibrosis, inflammatory disorders, and autoimmune diseases.

Cancer:

• Overexpression of ITGAV integrins, especially αvβ3 and αvβ5, is associated with increased tumor growth, metastasis, and resistance to apoptosis. These integrins are also involved in angiogenesis, which is critical for tumor progression. Integrin inhibitors targeting ITGAV, such as cilengitide, have been developed as potential therapies for cancer, although clinical trials have yielded mixed results.

Fibrotic Diseases:

• The role of αvβ6 and αvβ8 in TGF-β activation makes ITGAV integrins key players in the development of fibrotic diseases such as pulmonary fibrosis and liver fibrosis. Targeting ITGAV integrins or their downstream signaling pathways may offer therapeutic strategies to mitigate fibrosis.

Inflammatory and Autoimmune Disorders:

• ITGAV integrins are involved in the regulation of immune cell function, including phagocytosis and TGF-β activation, which can influence the development of inflammatory and autoimmune diseases. Dysregulated integrin activity may contribute to pathological inflammation in conditions like rheumatoid arthritis and inflammatory bowel disease.

Summary

ITGAV (Integrin subunit alpha V) is a versatile and multifunctional protein that plays a critical role in cell adhesion, migration, angiogenesis, immune regulation, and tumor progression. Structurally, ITGAV forms heterodimers with several β subunits, each of which imparts distinct ligand-binding capabilities and biological functions. ITGAV is involved in key physiological processes, such as wound healing, tissue repair, and immune responses, but its dysregulation can lead to pathological conditions, including cancer, fibrosis, and inflammatory diseases. As a result, ITGAV integrins have emerged as potential therapeutic targets in several diseases, with ongoing research aimed at further understanding their roles and developing integrin-based therapies.