title: Activation of Bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain.
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.
authors.affiliation: Molecular Biology Institute, University of California, Los Angeles 90095, USA.
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Tsukada
authors.forename: A
authors.initials: A
authors.lastname: Satterthwaite
authors.forename: M H
authors.initials: MH
authors.lastname: Havlik
authors.forename: H
authors.initials: H
authors.lastname: Park
authors.forename: K
authors.initials: K
authors.lastname: Takatsu
authors.forename: O N
authors.initials: ON
authors.lastname: Witte
mesh_terms: D016475:3T3 Cells; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D015870:Gene Expression; D051379:Mice; D008969:Molecular Sequence Data; D019000:Phosphotyrosine; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse