ITGB3 - integrin subunit beta 3 |Elisa - Clia - Antibody - Protein

Background

ITGB3 (Integrin Subunit Beta 3) encodes the β3 subunit of integrins, which are transmembrane receptors that mediate cell-cell and cell-extracellular matrix (ECM) interactions. Integrins are essential in diverse cellular processes, including cell adhesion, migration, signal transduction, immune responses, and angiogenesis. The ITGB3 protein partners with αIIb (encoded by ITGA2B) and αV (encoded by ITGAV) to form αIIbβ3 and αVβ3 integrins, respectively. These heterodimers are pivotal for platelet aggregation, thrombosis, wound healing, and interactions with extracellular matrix proteins like fibrinogen, fibronectin, and vitronectin.

ITGB3 is expressed in platelets, endothelial cells, and various tissues involved in cell movement and immune responses. Dysregulation or mutation of ITGB3 can lead to disorders such as Glanzmann thrombasthenia, affecting platelet function, or it can play a role in pathological conditions like cancer metastasis, where altered cell adhesion and migration are key.

Protein Structure

ITGB3 is a transmembrane glycoprotein that is 762 amino acids long. It is synthesized as a single polypeptide that undergoes post-translational modifications, including glycosylation, which is crucial for proper folding and function. ITGB3, as a member of the integrin family, has a structurally conserved domain organization. Its major structural features include:

Extracellular Domain:

• The extracellular domain of ITGB3 is approximately 700 amino acids in length and is responsible for binding ligands, such as fibrinogen, fibronectin, vitronectin, and other ECM proteins. The I-like domain in the β3 integrin is a key site for ligand recognition and binding. This domain interacts with divalent cations (Ca²⁺, Mg²⁺), which are required for integrin activation and ligand affinity modulation.
• ITGB3 partners with an α subunit (such as αIIb or αV) through non-covalent interactions, forming the αIIbβ3 or αVβ3 heterodimers. This association allows integrins to recognize the RGD (arginine-glycine-aspartic acid) motif in extracellular proteins, facilitating adhesion.

Transmembrane Domain:

• The transmembrane domain of ITGB3 spans the lipid bilayer and plays a role in transmitting signals from the extracellular environment to the cytoplasm. This transmembrane region, a single-pass α-helix, is crucial for stabilizing the dimerization of integrins and facilitating their conformational changes, which are critical for activation.

Cytoplasmic Domain:

• The cytoplasmic tail of ITGB3 is relatively short (approximately 47 amino acids) and mediates interactions with intracellular signaling molecules, such as talin, kindlin, and filamin, which regulate integrin activation, clustering, and linkage to the actin cytoskeleton.
• This intracellular domain is also involved in inside-out signaling, where intracellular signals modify integrin affinity for its ligands, and outside-in signaling, where extracellular ligand binding initiates intracellular signaling pathways.

Post-Translational Modifications:

• ITGB3 undergoes glycosylation, which helps in proper folding and function. Additionally, phosphorylation of the cytoplasmic domain, especially on tyrosine residues, regulates its signaling and interaction with cytoskeletal and signaling proteins.

Classification and Subtypes

ITGB3 belongs to the integrin family, specifically classified as a β integrin subunit. The integrins are a large family of heterodimeric receptors composed of an α and β subunit. The ITGB3 gene forms heterodimers with two different α subunits:

1. αIIbβ3 Integrin:

• This integrin is expressed predominantly in platelets and plays a central role in platelet aggregation and blood clot formation. αIIbβ3 binds fibrinogen during platelet activation, allowing the formation of a platelet plug at sites of vascular injury.

1. αVβ3 Integrin:

• This integrin is expressed in endothelial cells, osteoclasts, and various other cells. It is involved in angiogenesis, bone resorption, and tumor metastasis. αVβ3 binds to ECM proteins, including vitronectin, fibronectin, and osteopontin, contributing to processes like cell migration and survival.

Function and Biological Significance

ITGB3, as part of integrin receptors, mediates crucial biological processes, including cell adhesion, migration, thrombus formation, and angiogenesis. Its function can be divided according to the integrins it forms.

Platelet Aggregation and Hemostasis:

• In platelets, ITGB3 pairs with αIIb to form the αIIbβ3 integrin. This integrin is inactive on resting platelets but undergoes conformational activation during platelet activation (via inside-out signaling), allowing it to bind fibrinogen. Fibrinogen forms a bridge between platelets, facilitating platelet aggregation, which is essential for the formation of a blood clot to stop bleeding.
• Outside-in signaling through αIIbβ3 promotes platelet spreading, stabilization of the platelet plug, and recruitment of additional platelets.

Angiogenesis and Cell Migration:

• The αVβ3 integrin, expressed in endothelial cells, is critically involved in angiogenesis (the formation of new blood vessels), a process essential for tissue repair, wound healing, and tumor growth. αVβ3 mediates adhesion to vitronectin and other ECM proteins, enabling endothelial cells to migrate and form new blood vessels.
• In addition to angiogenesis, αVβ3 integrin facilitates the migration of various cell types, including cancer cells, contributing to processes like tumor invasion and metastasis.

Bone Resorption:

• In osteoclasts, αVβ3 integrin mediates attachment to the bone matrix, facilitating bone resorption. Osteoclasts degrade bone as part of normal bone remodeling and in pathological conditions such as osteoporosis.

Immune System:

• ITGB3 is also expressed in some immune cells and may play a role in immune responses by regulating cell adhesion, migration, and interactions with the ECM.

Clinical Issues

Glanzmann Thrombasthenia (GT):

• Mutations in ITGB3 lead to Glanzmann thrombasthenia, a rare autosomal recessive bleeding disorder characterized by defective platelet aggregation. Patients with GT have normal platelet counts but lack functional αIIbβ3 integrin, which results in impaired platelet aggregation and abnormal clot formation, leading to prolonged bleeding, especially after trauma or surgery.

Thrombosis:

• Abnormal activation of αIIbβ3 integrin can lead to excessive platelet aggregation, contributing to the formation of thrombi (blood clots). This can result in serious conditions like myocardial infarction (heart attack) or stroke. Antagonists of αIIbβ3, such as abciximab, are used as antiplatelet agents to prevent thrombosis during certain cardiovascular procedures.

Cancer Metastasis:

• The αVβ3 integrin is overexpressed in various cancers and plays a role in tumor progression, angiogenesis, and metastasis. By mediating cell adhesion and migration, αVβ3 integrin allows cancer cells to invade tissues and spread to distant organs. Inhibitors of αVβ3 integrin are being explored as potential anticancer therapies to block tumor angiogenesis and metastasis.

Osteoporosis:

• Since αVβ3 integrin is essential for osteoclast function, dysregulation of ITGB3 can lead to bone-related disorders. In osteoporosis, increased bone resorption due to overactive osteoclasts results in reduced bone density and increased fracture risk. Targeting αVβ3 integrin with specific inhibitors may help treat osteoporosis by reducing excessive bone degradation.

Summary

ITGB3 encodes the β3 subunit of integrins, which forms heterodimers with αIIb and αV to produce αIIbβ3 and αVβ3 integrins. These integrins play essential roles in platelet aggregation, angiogenesis, cell migration, and bone resorption. ITGB3's structure includes an extracellular ligand-binding domain, a transmembrane domain, and a cytoplasmic tail that transmits signals between the ECM and the intracellular environment. Mutations or dysregulation of ITGB3 result in various clinical conditions, including Glanzmann thrombasthenia, thrombosis, cancer metastasis, and osteoporosis. ITGB3 remains a key target for therapeutic interventions aimed at modulating integrin function in diseases ranging from cardiovascular disorders to cancer.