Activation of bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain

Tianjian Li, Satoshi Tsukada, Anne Satterthwaite, Marie H. Havlik, Hyunsun Park, Kiyoshi Takatsu, Owen N. Witte

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Abstract

Bruton's tyrosine kinase (BTK) is a nonreceptor tyrosine kinase critical for B cell development and function. Mutations in BTK result in X-linked agammaglobulinemia (XLA) in humans and X-linked Immunodeficiency (xid) in mice. Using a random mutagenesis scheme, we isolated a gain-of-function mutant called BTK* whose expression drives growth of NIH 3T3 cells In soft agar. BTK* results from a single point mutation In the pleckstrin homology (PH) domain, where a Glu is replaced by Lys at residue 41. BTK* shows an increase In phosphorylation on tyrosine residues and an increase in membrane targeting. Transforming activity requires kinase activity, a putative autophosphorylation site, and a functional PH domain. Mutation of the SH2 or SH3 domains did not affect the activity of BTK*. Expression of BTK* could also relieve IL-5 dependence of a B lineage cell line. These results show that transformation activation and regulation of BTK are critically dependent on the PH domain.

Original languageEnglish (US)
Pages (from-to)451-460
Number of pages10
JournalImmunity
Volume2
Issue number5
DOIs
Publication statusPublished - 1995

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ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Infectious Diseases

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