LAUSR

Signaling Bruton's tyrosine kinase (Btk) is a key player in B cell signaling and is a target in treating some lymphomas and leukemias. An early step in the signaling pathway is the generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3), which recruits Btk to the membrane through binding its pleckstrin homology and Tec homology (PH-TH) module. Chung et al. show that recruitment alone does not activate Btk. By measuring molecular diffusion and adsorption kinetics of wild-type and mutant PH-TH modules, they show that while PIP3 binding to a canonical site allows membrane recruitment, binding to a second PIP3 favors dimerization. This is required for activation and allows a switch-like response to PIP3 levels. By contrast, although the kinases are in the same family, the mechanism is not conserved in T cell signaling. Proc. Natl Acad. Sci. U.S.A. 10.1073/pnas.1819309116 (2019).