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

21 Scopus citations

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 1 2008

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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