This document describes a study where researchers isolated a gain-of-function mutant of Bruton's tyrosine kinase (BTK) called BTK* through random mutagenesis. BTK* results from a single point mutation in the pleckstrin homology (PH) domain that replaces a glutamate with a lysine at residue 41. BTK* shows increased phosphorylation, increased membrane targeting, and can drive cell growth in soft agar. The transforming activity requires kinase activity and an intact PH domain. Expression of BTK* can also relieve interleukin-5 dependence in a B cell line. The results demonstrate that the PH domain critically regulates BTK transformation and activation.