Bruton tyrosine kinase (BTK)

Bruton tyrosine kinase (BTK) is a cytoplasmic nonreceptor protein tyrosine kinase crucial for B cell development and function, particularly in B-cell receptor signaling. It contains an amino terminal pleckstrin homology (PH) domain, a proline-rich TEC homology (TH) domain, SH2 and SH3 domains, and a protein kinase domain. The PH domain binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which induces BTK to phosphorylate phospholipase C (PLC), triggering a signaling cascade essential for B-cell development and function. BTK is required for transmitting signals from the pre-B cell receptor and plays a role in mast cell activation. Named after Ogden Bruton, who described X-linked agammaglobulinemia (XLA), mutations in the BTK gene cause this severe primary immunodeficiency disease. BTK has become an attractive therapeutic target in B-cell malignancies, autoimmune disorders, and inflammatory conditions. Multiple isoforms exist, including the original BTK-A and the truncated p65BTK. BTK activation involves a complex mechanism where the PH-TH module stabilizes an inactive conformation, and activation can be triggered by membranes containing PIP3 or by IP6, potentially involving dimerization.

BTK inhibitors block the B-cell receptor signaling pathway, triggering the death of cancer cells. They bind to the active site of BTK, preventing its phosphorylation and inhibiting downstream signaling cascades.