Disease relevance of Btk

• Bruton's tyrosine kinase (Btk) is encoded by the gene that when mutated causes the primary immunodeficiency disease X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice [1].

High impact information on Btk

• Two amino acids in the PLC-delta 1 PH domain that contact Ins(1,4,5)P3 have counterparts in the Bruton's tyrosine kinase (Btk) PH domain, where mutational changes cause inherited agammaglobulinemia, suggesting a mechanism for loss of function in Btk mutants [2].
• ATP activates the Btk tyrosine kinase, Tec, and induces its association with PLCgamma [3].
• The activity of Btk is partially regulated by transphosphorylation within its kinase domain by Src family kinases at residue Tyr-551 and subsequent autophosphorylation at Tyr-223 [4].
• The Btk PH domain can bind in vitro to several lipid end products of the phosphatidylinositol 3-kinase (PI 3-kinase) family including phosphatidylinositol 3,4,5-trisphosphate [4].
• Bruton's tyrosine kinase (Btk) is essential for normal B lymphocyte development and function [4].

Chemical compound and disease context of Btk

• We identified the cd gamma kinase by Western blotting and by partial phosphopeptide mapping as Btk, the B-cell tyrosine kinase found to be defective in X-linked agammaglobulinemia [5].

Biological context of Btk

• This activation correlates with new sites of phosphorylation on Btk identified by two-dimensional phosphopeptide mapping [4].
• In addition to the GAP catalytic domain, Gap1m has two domains with sequence closely related to those of the phospholipid-binding domain of synaptotagmin and a region with similarity to the unique domain of Btk tyrosine kinase [6].
• The stable expression of Lyn-PLCgamma2 was not accompanied by an increase in substrate hydrolysis in resting cells, which followed stimulation and specifically required the presence and/or activation of Syk, Btk, phosphoinositide 3-kinase but not BLNK, as established using deficient cell lines or specific inhibitors [7].

Anatomical context of Btk

• Mutations affecting Btk block B-lymphocyte development [1].
• Activation correlates with Btk association with cellular membranes [4].
• Etk (also called Bmx) is a member of the Btk tyrosine kinase family and is expressed in a variety of hematopoietic, epithelial, and endothelial cells [8].
• A fraction of Bruton's tyrosine kinase (Btk) co-localizes with actin fibers upon stimulation of mast cells via the high affinity IgE receptor (FcepsilonRI) [9].
• The negative regulatory effect of Pin1 was observed both in cell lines and in Pin(-/-) mice and was found to be dependent on a functionally intact Btk [10].

Associations of Btk with chemical compounds

• Activation of Btk as monitored by elevation of phosphotyrosine content and a cellular transformation response was dramatically enhanced by coexpressing a weakly activated allele of Src (E378G) and the two subunits of PI 3-kinase-gamma [4].
• Using a phosphomitotic antibody, it was found that Btk harbors a bona fide MPM2 epitope corresponding to a phosphorylated serine or threonine residue followed by a proline [10].

Other interactions of Btk

• Activation of Btk was dependent on the catalytic activity of all three enzymes and an intact Btk PH domain and Src transphosphorylation site [4].

References