ITGB4 - integrin subunit beta 4 | Elisa - Clia - Antibody - Protein

Background

Integrin subunit beta 4 (ITGB4) is a vital cell-adhesion molecule in the integrin family, specifically expressed in epithelial cells, where it plays a critical role in cell adhesion, signal transduction, and cellular responses to external stimuli. ITGB4 is notable for its involvement in forming hemidesmosomes, specialized structures that attach epithelial cells to the basement membrane, thereby contributing to tissue integrity, resilience, and structural stability. ITGB4 often pairs with the alpha 6 integrin subunit (forming the α6β4 integrin complex), allowing these integrins to specifically interact with laminins in the extracellular matrix. These interactions mediate a variety of essential biological processes, including cell adhesion, migration, differentiation, and survival. Due to its essential role in maintaining epithelial tissue structure and regulating cellular signaling, dysregulation or mutations in ITGB4 have been associated with a range of disorders, including epidermolysis bullosa and certain cancers.

Protein Structure

ITGB4 is a large transmembrane glycoprotein consisting of 1822 amino acids with a molecular weight of approximately 200 kDa. Structurally, ITGB4 differs from other integrin β subunits due to its extended intracellular domain, which facilitates unique interactions with cytoskeletal and signaling proteins.

Extracellular Domain:

• The extracellular domain of ITGB4 is responsible for ligand binding and is composed of several functional motifs, including calcium-binding sites that stabilize the integrin structure and aid in conformational regulation. The β4 subunit forms a heterodimer with the α6 subunit to create the α6β4 integrin, which has a high affinity for laminin-5 (Laminin-332) in the basement membrane.
• The structure also contains epidermal growth factor (EGF)-like domains in the extracellular segment, which contribute to the structural stability and ligand-binding capability of ITGB4.
• This domain also includes regions for interaction with extracellular matrix components, facilitating its primary role in mediating cell-matrix adhesion and signaling processes.

Transmembrane Domain:

• The transmembrane segment of ITGB4 is a hydrophobic α-helical region that spans the plasma membrane, anchoring the integrin to the cell surface. This segment contributes to the structural integrity and spatial orientation of the integrin complex.

Intracellular Domain:

• The intracellular domain of ITGB4 is one of the largest among integrin β subunits and is crucial for its signaling functions. It contains two unique regions: the cytoplasmic tail and the cytoplasmic domain extension.
• The cytoplasmic tail interacts with cytoskeletal components such as plectin and BPAG1e (bullous pemphigoid antigen 1), which link ITGB4 to intermediate filaments in hemidesmosomes, stabilizing cell attachment to the extracellular matrix.
• The extended cytoplasmic domain also interacts with signaling molecules, including Src family kinases and phosphoinositide 3-kinase (PI3K), allowing ITGB4 to participate in pathways that regulate cell survival, proliferation, and migration.
• Phosphorylation sites within the intracellular domain enable ITGB4 to undergo post-translational modifications, regulating its interaction with signaling partners and influencing cellular responses to environmental cues.

Classification and Subtypes

ITGB4 is classified within the integrin beta family as one of the unique beta subunits due to its specific pairing and specialized role in epithelial adhesion.

Integrin Subunit Beta 4 (β4):

• Heterodimer Pairing: ITGB4 pairs exclusively with the alpha 6 integrin (ITGA6) subunit to form the α6β4 integrin heterodimer. This specific combination confers a high affinity for laminin-binding, which distinguishes α6β4 from other integrin complexes.

Distinct Structural Features:

• Unlike most integrin β subunits, ITGB4 has a large intracellular domain that enables its unique interaction with cytoskeletal proteins and signal transduction molecules. This feature makes ITGB4 essential in epithelial cell stability and adhesion.

Function and Biological Significance

Epithelial Cell Adhesion and Tissue Integrity:

• The primary function of ITGB4 is to stabilize epithelial cells by forming hemidesmosomes, attaching them firmly to the basement membrane. This structural attachment is essential for maintaining tissue integrity, particularly in the skin, lungs, and other epithelial-rich organs.
• By forming hemidesmosomes, ITGB4 enables tissues to withstand mechanical stress, thereby contributing to the resilience of epithelial barriers.

Signal Transduction:

• Beyond adhesion, ITGB4 plays a significant role in cellular signaling pathways, impacting cell survival, proliferation, and migration. When ITGB4 interacts with extracellular matrix components, it initiates intracellular signaling cascades involving PI3K, Akt, and FAK (focal adhesion kinase), which are crucial for epithelial cell survival and migration.
• Phosphorylation of the intracellular domain of ITGB4 also activates signaling molecules such as Src family kinases, leading to cellular responses that support tissue repair, regeneration, and response to injury.

Role in Cell Migration and Cancer Metastasis:

• ITGB4’s interactions with the cytoskeleton and signaling molecules facilitate cellular motility, particularly during wound healing and in certain pathological conditions like cancer. Increased expression of ITGB4 has been observed in some cancers, where it promotes cancer cell migration and invasion.
• ITGB4 signaling can enhance the migration of cancer cells from the primary tumor to adjacent tissues, contributing to metastasis. This function underscores ITGB4’s significance in cancer biology, particularly in cancers originating from epithelial tissues.

Clinical Issues

Epidermolysis Bullosa:

• Mutations in the ITGB4 gene can lead to junctional epidermolysis bullosa (JEB), a severe skin disorder characterized by blistering due to the detachment of epithelial cells from the basement membrane. These mutations disrupt the formation of functional hemidesmosomes, leading to fragile skin that is prone to blistering and damage from minor friction or trauma.

Cancer Progression and Metastasis:

• ITGB4 has been implicated in the progression of several cancers, including breast, lung, and pancreatic cancers. High ITGB4 expression levels in these cancers have been associated with increased invasive capabilities, likely due to ITGB4’s role in cell migration and survival signaling. Additionally, ITGB4 is thought to aid tumor cells in overcoming cellular stress, enhancing their survival and facilitating metastasis.
• Targeting ITGB4-mediated pathways is a potential therapeutic strategy in cancers where ITGB4 overexpression contributes to aggressive tumor behavior.

Chronic Inflammatory Diseases:

• ITGB4 has been associated with chronic inflammatory diseases such as psoriasis and inflammatory bowel disease (IBD). In these conditions, abnormal ITGB4 expression in epithelial cells can contribute to inflammation by disrupting tissue barriers, enhancing cell migration, or modulating immune cell interactions.

Summary

ITGB4 (integrin subunit beta 4) is a unique and essential integrin predominantly expressed in epithelial cells, where it primarily pairs with ITGA6 to form the α6β4 integrin complex. This complex mediates critical interactions with laminins in the extracellular matrix, facilitating epithelial cell adhesion to the basement membrane. Structurally, ITGB4 is distinct due to its large intracellular domain, which supports interaction with cytoskeletal proteins like plectin and signaling proteins, enabling both adhesion and intracellular signaling.

The biological roles of ITGB4 include maintaining tissue integrity, supporting cellular responses through signaling pathways, and facilitating cell migration during processes such as wound healing and cancer metastasis. Clinically, ITGB4 dysfunction is associated with disorders like junctional epidermolysis bullosa, characterized by weakened epithelial integrity and blistering skin. Furthermore, ITGB4 is linked to cancer progression due to its role in cell migration and survival, particularly in aggressive epithelial-origin cancers. Consequently, ITGB4 represents a significant target for therapeutic intervention in conditions where its dysregulation contributes to disease, making it a focus in cancer and chronic inflammatory disease research.