Constitutive membrane association potentiates activation of Bruton tyrosine kinase

Tianjian Li, David J. Rawlings, Hyunsun Park, Roberta M. Kato, Owen N. Witte, Anne B. Satterthwaite

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Mutations in the nonreceptor tyrosine kinase Btk result in the B cell immunodeficiencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Genetic and biochemical evidence implicates Btk as a key component of several B cell signaling pathways. Activation of Btk by a point mutation (E41K) within the PH domain (Btk(*)) results in fibroblast transformation and is correlated with increased membrane localization of Btk. When wild type Btk is activated by coexpression with Lyn, the tyrosine phosphorylated pool of Btk is highly enriched in the membrane fraction. To determine whether membrane association is sufficient to activate Btk, we targeted Btk to the plasma membrane using a series of fusion proteins including GagBtk, CD16Btk and CD4Btk. Constitutive membrane association greatly enhanced the ability of Btk to transform Rat2 fibroblasts in the presence of high levels of Src activity. All membrane targeted forms of Btk were highly tyrosine phosphorylated. Transformation required membrane localization, Btk kinase activity, transphosphorylation by Src family kinases, and an intact SH2 domain but not the PH or SH3 domains. These data suggest that membrane localization is a critical early step in Btk activation.

Original languageEnglish (US)
Pages (from-to)1375-1383
Number of pages9
JournalOncogene
Volume15
Issue number12
StatePublished - 1997

Fingerprint

Membranes
src Homology Domains
Tyrosine
B-Lymphocytes
Fibroblasts
src-Family Kinases
Agammaglobulinaemia tyrosine kinase
Point Mutation
Protein-Tyrosine Kinases
Molecular Biology
Phosphotransferases
Cell Membrane
Mutation
Proteins
Pleckstrin Homology Domains

Keywords

  • Btk
  • Membrane targeting
  • Pleckstrin homology domain
  • Transformation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Li, T., Rawlings, D. J., Park, H., Kato, R. M., Witte, O. N., & Satterthwaite, A. B. (1997). Constitutive membrane association potentiates activation of Bruton tyrosine kinase. Oncogene, 15(12), 1375-1383.

Constitutive membrane association potentiates activation of Bruton tyrosine kinase. / Li, Tianjian; Rawlings, David J.; Park, Hyunsun; Kato, Roberta M.; Witte, Owen N.; Satterthwaite, Anne B.

In: Oncogene, Vol. 15, No. 12, 1997, p. 1375-1383.

Research output: Contribution to journalArticle

Li, T, Rawlings, DJ, Park, H, Kato, RM, Witte, ON & Satterthwaite, AB 1997, 'Constitutive membrane association potentiates activation of Bruton tyrosine kinase', Oncogene, vol. 15, no. 12, pp. 1375-1383.
Li T, Rawlings DJ, Park H, Kato RM, Witte ON, Satterthwaite AB. Constitutive membrane association potentiates activation of Bruton tyrosine kinase. Oncogene. 1997;15(12):1375-1383.
Li, Tianjian ; Rawlings, David J. ; Park, Hyunsun ; Kato, Roberta M. ; Witte, Owen N. ; Satterthwaite, Anne B. / Constitutive membrane association potentiates activation of Bruton tyrosine kinase. In: Oncogene. 1997 ; Vol. 15, No. 12. pp. 1375-1383.
@article{45c1532e3229411bb95ee87d95710fd3,
title = "Constitutive membrane association potentiates activation of Bruton tyrosine kinase",
abstract = "Mutations in the nonreceptor tyrosine kinase Btk result in the B cell immunodeficiencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Genetic and biochemical evidence implicates Btk as a key component of several B cell signaling pathways. Activation of Btk by a point mutation (E41K) within the PH domain (Btk(*)) results in fibroblast transformation and is correlated with increased membrane localization of Btk. When wild type Btk is activated by coexpression with Lyn, the tyrosine phosphorylated pool of Btk is highly enriched in the membrane fraction. To determine whether membrane association is sufficient to activate Btk, we targeted Btk to the plasma membrane using a series of fusion proteins including GagBtk, CD16Btk and CD4Btk. Constitutive membrane association greatly enhanced the ability of Btk to transform Rat2 fibroblasts in the presence of high levels of Src activity. All membrane targeted forms of Btk were highly tyrosine phosphorylated. Transformation required membrane localization, Btk kinase activity, transphosphorylation by Src family kinases, and an intact SH2 domain but not the PH or SH3 domains. These data suggest that membrane localization is a critical early step in Btk activation.",
keywords = "Btk, Membrane targeting, Pleckstrin homology domain, Transformation",
author = "Tianjian Li and Rawlings, {David J.} and Hyunsun Park and Kato, {Roberta M.} and Witte, {Owen N.} and Satterthwaite, {Anne B.}",
year = "1997",
language = "English (US)",
volume = "15",
pages = "1375--1383",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - Constitutive membrane association potentiates activation of Bruton tyrosine kinase

AU - Li, Tianjian

AU - Rawlings, David J.

AU - Park, Hyunsun

AU - Kato, Roberta M.

AU - Witte, Owen N.

AU - Satterthwaite, Anne B.

PY - 1997

Y1 - 1997

N2 - Mutations in the nonreceptor tyrosine kinase Btk result in the B cell immunodeficiencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Genetic and biochemical evidence implicates Btk as a key component of several B cell signaling pathways. Activation of Btk by a point mutation (E41K) within the PH domain (Btk(*)) results in fibroblast transformation and is correlated with increased membrane localization of Btk. When wild type Btk is activated by coexpression with Lyn, the tyrosine phosphorylated pool of Btk is highly enriched in the membrane fraction. To determine whether membrane association is sufficient to activate Btk, we targeted Btk to the plasma membrane using a series of fusion proteins including GagBtk, CD16Btk and CD4Btk. Constitutive membrane association greatly enhanced the ability of Btk to transform Rat2 fibroblasts in the presence of high levels of Src activity. All membrane targeted forms of Btk were highly tyrosine phosphorylated. Transformation required membrane localization, Btk kinase activity, transphosphorylation by Src family kinases, and an intact SH2 domain but not the PH or SH3 domains. These data suggest that membrane localization is a critical early step in Btk activation.

AB - Mutations in the nonreceptor tyrosine kinase Btk result in the B cell immunodeficiencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Genetic and biochemical evidence implicates Btk as a key component of several B cell signaling pathways. Activation of Btk by a point mutation (E41K) within the PH domain (Btk(*)) results in fibroblast transformation and is correlated with increased membrane localization of Btk. When wild type Btk is activated by coexpression with Lyn, the tyrosine phosphorylated pool of Btk is highly enriched in the membrane fraction. To determine whether membrane association is sufficient to activate Btk, we targeted Btk to the plasma membrane using a series of fusion proteins including GagBtk, CD16Btk and CD4Btk. Constitutive membrane association greatly enhanced the ability of Btk to transform Rat2 fibroblasts in the presence of high levels of Src activity. All membrane targeted forms of Btk were highly tyrosine phosphorylated. Transformation required membrane localization, Btk kinase activity, transphosphorylation by Src family kinases, and an intact SH2 domain but not the PH or SH3 domains. These data suggest that membrane localization is a critical early step in Btk activation.

KW - Btk

KW - Membrane targeting

KW - Pleckstrin homology domain

KW - Transformation

UR - http://www.scopus.com/inward/record.url?scp=0030771737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030771737&partnerID=8YFLogxK

M3 - Article

C2 - 9333013

AN - SCOPUS:0030771737

VL - 15

SP - 1375

EP - 1383

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 12

ER -