AXL receptor tyrosine kinase | Elisa - Clia - Antibody - Protein

Background

AXL receptor tyrosine kinase (AXL) is a member of the TAM (Tyro3, AXL, and MERTK) receptor tyrosine kinase family. This family of receptors is characterized by their roles in cell survival, proliferation, migration, and immune regulation. AXL was first identified as a transforming gene in chronic myeloid leukemia, and since then, it has been implicated in a variety of physiological and pathological processes, including cancer, fibrosis, and immune response modulation.

AXL and its ligands are widely expressed in various tissues, including the cardiovascular, immune, and nervous systems. The primary ligand for AXL is growth arrest-specific 6 (Gas6), a vitamin K-dependent protein that mediates the receptor's activation. Binding of Gas6 to AXL triggers a cascade of downstream signaling events that influence cellular behaviors and fate decisions.

Protein Structure

The AXL protein is composed of several distinct domains that facilitate its diverse functions:

1. Extracellular Domain: This region contains two immunoglobulin-like (Ig-like) domains and two fibronectin type III (FNIII) domains. The Ig-like domains are crucial for binding to its ligand, Gas6, while the FNIII domains contribute to receptor dimerization and stability.
2. Transmembrane Domain: A single hydrophobic alpha-helix that spans the cell membrane, anchoring the receptor in place.
3. Intracellular Tyrosine Kinase Domain: This domain possesses intrinsic kinase activity, which is activated upon ligand binding and receptor dimerization. The kinase domain autophosphorylates specific tyrosine residues, creating docking sites for downstream signaling molecules.

Classification and Subtypes

AXL is one of three members of the TAM receptor family. The other two members are Tyro3 and MERTK. While all three receptors share similar structural features and overlapping functions, they also exhibit distinct expression patterns and physiological roles.

1. Tyro3: Primarily involved in the nervous system and reproductive organs, Tyro3 plays a critical role in neural development and immune regulation.
2. MERTK: Predominantly expressed in macrophages and other immune cells, MERTK is essential for the clearance of apoptotic cells and modulation of immune responses.

Function and Biological Significance

AXL plays a multifaceted role in various biological processes:

1. Cell Survival and Proliferation: AXL signaling promotes cell survival and proliferation through the activation of the PI3K-Akt and MAPK pathways. These pathways are essential for protecting cells from apoptosis and promoting cell cycle progression.
2. Migration and Invasion: AXL enhances cellular migration and invasion, particularly in cancer cells, by modulating the cytoskeleton and extracellular matrix interactions. This property is vital for processes like wound healing and cancer metastasis.
3. Immune Regulation: AXL modulates immune responses by dampening inflammatory signaling and promoting the clearance of apoptotic cells. This function helps maintain immune homeostasis and prevent chronic inflammation.
4. Fibrosis: AXL contributes to fibrotic responses in tissues by promoting the differentiation of fibroblasts into myofibroblasts and the deposition of extracellular matrix components.

Clinical Issues

The dysregulation of AXL is associated with several diseases, particularly cancer and fibrotic disorders:

1. Cancer: Overexpression or hyperactivation of AXL is observed in various cancers, including breast, lung, pancreatic, and prostate cancers. AXL promotes tumorigenesis by enhancing cancer cell survival, proliferation, migration, and invasion. Additionally, AXL-mediated signaling can confer resistance to conventional therapies, making it a target for novel cancer treatments. AXL inhibitors are currently being explored in clinical trials as potential therapeutic agents.
2. Fibrosis: AXL is implicated in the progression of fibrotic diseases such as idiopathic pulmonary fibrosis and liver cirrhosis. Inhibition of AXL signaling has shown promise in reducing fibrotic tissue formation and improving tissue function in preclinical models.
3. Immune Disorders: Given its role in immune regulation, AXL dysfunction can contribute to autoimmune diseases and chronic inflammatory conditions. Modulating AXL activity holds potential for treating such disorders by restoring immune balance.

Summary

AXL receptor tyrosine kinase is a pivotal regulator of cell survival, proliferation, migration, and immune responses. Structurally characterized by its extracellular Ig-like and FNIII domains, a transmembrane segment, and an intracellular kinase domain, AXL orchestrates a variety of signaling pathways that influence cellular behaviors. Its involvement in cancer progression, fibrotic diseases, and immune regulation underscores its significance in health and disease. Targeting AXL with specific inhibitors presents a promising therapeutic strategy for treating cancers and other conditions associated with AXL dysregulation. Understanding the precise mechanisms and contexts of AXL function continues to be an area of active research, with significant implications for developing novel clinical interventions.