Allosteric inhibition of the nonMyristoylated c-Abl tyrosine kinase by phosphopeptides derived from Abi1/Hssh3bp1

Xiaoling Xiong, Ping Cui, Sajjad Hossain, Rong Xu, Brian Warner, Xinhua Guo, Xiuli An, Asim K. Debnath, David Cowburn, Leszek Kotula

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Here we report c-Abl kinase inhibition mediated by a phosphotyrosine located in trans in the c-Abl substrate, Abi1. The mechanism, which is pertinent to the nonmyristoylated c-Abl kinase, involves high affinity concurrent binding of the phosphotyrosine pY213 to the Abl SH2 domain and binding of a proximal PXXP motif to the Abl SH3 domain. Abi1 regulation of c-Abl in vivo appears to play a critical role, as demonstrated by inhibition of pY412 phosphorylation of the nonmyristoylated Abl by coexpression of Abi1. Pervanadate-induced c-Abl kinase activity was also reduced upon expression of the wild type Abi1 but not by expression of the Y213 to F213 mutant Abi1 in LNCaP cells, which are naturally deficient in the regulatory pY213. Our findings suggest a novel mechanism by which Abl kinase is regulated in cells.

Original languageEnglish (US)
Pages (from-to)737-747
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1783
Issue number5
DOIs
StatePublished - May 2008

Fingerprint

Phosphopeptides
Protein-Tyrosine Kinases
Phosphotransferases
Phosphotyrosine
src Homology Domains
Phosphorylation

Keywords

  • Abi1
  • Allosteric mechanism
  • c-Abl
  • Hssh3bp1
  • SH3 and SH2 domain
  • Tyrosine kinase activity

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Biophysics

Cite this

Allosteric inhibition of the nonMyristoylated c-Abl tyrosine kinase by phosphopeptides derived from Abi1/Hssh3bp1. / Xiong, Xiaoling; Cui, Ping; Hossain, Sajjad; Xu, Rong; Warner, Brian; Guo, Xinhua; An, Xiuli; Debnath, Asim K.; Cowburn, David; Kotula, Leszek.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1783, No. 5, 05.2008, p. 737-747.

Research output: Contribution to journalArticle

Xiong, Xiaoling ; Cui, Ping ; Hossain, Sajjad ; Xu, Rong ; Warner, Brian ; Guo, Xinhua ; An, Xiuli ; Debnath, Asim K. ; Cowburn, David ; Kotula, Leszek. / Allosteric inhibition of the nonMyristoylated c-Abl tyrosine kinase by phosphopeptides derived from Abi1/Hssh3bp1. In: Biochimica et Biophysica Acta - Molecular Cell Research. 2008 ; Vol. 1783, No. 5. pp. 737-747.
@article{cd1127eaa0b6490fbf4d1a427ecc807e,
title = "Allosteric inhibition of the nonMyristoylated c-Abl tyrosine kinase by phosphopeptides derived from Abi1/Hssh3bp1",
abstract = "Here we report c-Abl kinase inhibition mediated by a phosphotyrosine located in trans in the c-Abl substrate, Abi1. The mechanism, which is pertinent to the nonmyristoylated c-Abl kinase, involves high affinity concurrent binding of the phosphotyrosine pY213 to the Abl SH2 domain and binding of a proximal PXXP motif to the Abl SH3 domain. Abi1 regulation of c-Abl in vivo appears to play a critical role, as demonstrated by inhibition of pY412 phosphorylation of the nonmyristoylated Abl by coexpression of Abi1. Pervanadate-induced c-Abl kinase activity was also reduced upon expression of the wild type Abi1 but not by expression of the Y213 to F213 mutant Abi1 in LNCaP cells, which are naturally deficient in the regulatory pY213. Our findings suggest a novel mechanism by which Abl kinase is regulated in cells.",
keywords = "Abi1, Allosteric mechanism, c-Abl, Hssh3bp1, SH3 and SH2 domain, Tyrosine kinase activity",
author = "Xiaoling Xiong and Ping Cui and Sajjad Hossain and Rong Xu and Brian Warner and Xinhua Guo and Xiuli An and Debnath, {Asim K.} and David Cowburn and Leszek Kotula",
year = "2008",
month = "5",
doi = "10.1016/j.bbamcr.2008.01.028",
language = "English (US)",
volume = "1783",
pages = "737--747",
journal = "Biochimica et Biophysica Acta - Molecular Cell Research",
issn = "0167-4889",
publisher = "Elsevier",
number = "5",

}

TY - JOUR

T1 - Allosteric inhibition of the nonMyristoylated c-Abl tyrosine kinase by phosphopeptides derived from Abi1/Hssh3bp1

AU - Xiong, Xiaoling

AU - Cui, Ping

AU - Hossain, Sajjad

AU - Xu, Rong

AU - Warner, Brian

AU - Guo, Xinhua

AU - An, Xiuli

AU - Debnath, Asim K.

AU - Cowburn, David

AU - Kotula, Leszek

PY - 2008/5

Y1 - 2008/5

N2 - Here we report c-Abl kinase inhibition mediated by a phosphotyrosine located in trans in the c-Abl substrate, Abi1. The mechanism, which is pertinent to the nonmyristoylated c-Abl kinase, involves high affinity concurrent binding of the phosphotyrosine pY213 to the Abl SH2 domain and binding of a proximal PXXP motif to the Abl SH3 domain. Abi1 regulation of c-Abl in vivo appears to play a critical role, as demonstrated by inhibition of pY412 phosphorylation of the nonmyristoylated Abl by coexpression of Abi1. Pervanadate-induced c-Abl kinase activity was also reduced upon expression of the wild type Abi1 but not by expression of the Y213 to F213 mutant Abi1 in LNCaP cells, which are naturally deficient in the regulatory pY213. Our findings suggest a novel mechanism by which Abl kinase is regulated in cells.

AB - Here we report c-Abl kinase inhibition mediated by a phosphotyrosine located in trans in the c-Abl substrate, Abi1. The mechanism, which is pertinent to the nonmyristoylated c-Abl kinase, involves high affinity concurrent binding of the phosphotyrosine pY213 to the Abl SH2 domain and binding of a proximal PXXP motif to the Abl SH3 domain. Abi1 regulation of c-Abl in vivo appears to play a critical role, as demonstrated by inhibition of pY412 phosphorylation of the nonmyristoylated Abl by coexpression of Abi1. Pervanadate-induced c-Abl kinase activity was also reduced upon expression of the wild type Abi1 but not by expression of the Y213 to F213 mutant Abi1 in LNCaP cells, which are naturally deficient in the regulatory pY213. Our findings suggest a novel mechanism by which Abl kinase is regulated in cells.

KW - Abi1

KW - Allosteric mechanism

KW - c-Abl

KW - Hssh3bp1

KW - SH3 and SH2 domain

KW - Tyrosine kinase activity

UR - http://www.scopus.com/inward/record.url?scp=41949113371&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41949113371&partnerID=8YFLogxK

U2 - 10.1016/j.bbamcr.2008.01.028

DO - 10.1016/j.bbamcr.2008.01.028

M3 - Article

C2 - 18328268

AN - SCOPUS:41949113371

VL - 1783

SP - 737

EP - 747

JO - Biochimica et Biophysica Acta - Molecular Cell Research

JF - Biochimica et Biophysica Acta - Molecular Cell Research

SN - 0167-4889

IS - 5

ER -