Recombinant Human BTK His-tag Protein, CF

Bruton tyrosine kinase (BTK), also known as Agammaglobulinemia tyrosine kinase (ATK) and B-cell progenitor kinase (BPK), is one of five members of the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family of cytoplasmic non-receptor tyrosine kinases (1,2) that is primarily expressed in B-lymphocytes. BTK, like others in this family, contains a characteristic N-terminal pleckstrin homology (PH) domain as well as a TEC homology domain with three regions including a Btk homology region and two proline-rich regions. In addition, BTK contains two Src homology domains that mediate binding events and a C-terminal kinase domain (1) with a conserved catalytic domain with an ATP binding site within the cleft of two lobes at the N-terminal and C-terminal regions (1,2). BTK is activated by phosphorylation by SYK or SRC family kinases and then subsequent autophosphorylation after recruitment to the membrane through its interaction with PIP3 production resulting from B cell antigen receptor activation (2). Mutations in the human btk gene were found to cause X-linked agammaglobulinemia (XLA), a male immune deficiency disorder characterized by a lack of mature, immunoglobulin-producing, peripheral B cells (3,4). Its activation is known to be involved in signal transduction pathways regulating survival, activation, proliferation, and also differentiation of B lineage lymphoid cells (1, 3-5).  Consequently BTK is critical for the survival of leukemic cells in various B cell malignancies including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL)(2,6,7). Inhibition of BTK is a promising target for therapeutics for B-cell malignancies given initial small-molecule inhibitors showed excellent anti-tumor activity in clinical studies (8) and their success in therapeutic application for CLL and small lymphocytic leukemia (SLL)(9).  Significant interest remains in the development of higher specificity BTK inhibitors with less off-target activity (10,11) as well as combination inhibitors targeting other kinases or other proteins targets (2,12-14) in addition to BTK in B-cell malignancy. In addition, ectopic expression of BTK has been observed in various solid tumors making BTK a therapeutic target of interest in a broader context for the role the kinase may play in the tumor microenvironment (2,15).