The N-terminal domain of the non-receptor tyrosine kinase ABL confers protein instability and suppresses tumorigenesis

Zhengwei Yan, Karthigayan Shanmugasundaram, Dongwen Ma, Jiayu Luo, Shiwen Luo, Hai Rao

Research output: Contribution to journalArticle

Abstract

Chromosome translocation can lead to chimeric proteins that may become oncogenic drivers. A classic example is the fusion of the BCR activator of RhoGEF and GTPase and the ABL proto-oncogene nonreceptor tyrosine kinase, a result of a chromosome abnormality (Philadelphia chromosome) that causes leukemia. To unravel the mechanism underlying BCR-ABL-mediated tumorigenesis, here we compared the stability of ABL and the BCR-ABL fusion. Using protein degradation, cell proliferation, 5-ethynyl-2-deoxyuridine, and apoptosis assays, along with xenograft tumor analysis, we found that the N-terminal segment of ABL, which is lost in the BCR-ABL fusion, confers degradation capacity that is promoted by SMAD-specific E3 ubiquitin protein ligase 1. We further demonstrate that the N-terminal deletion renders ABL more stable and stimulates cell growth and tumorigenesis. The findings of our study suggest that altered protein stability may contribute to chromosome translocation-induced cancer development.

Original languageEnglish (US)
Pages (from-to)9069-9075
Number of pages7
JournalThe Journal of biological chemistry
Volume295
Issue number27
DOIs
StatePublished - Jul 3 2020

Keywords

  • ABL kinase
  • ABL proto-oncogene non-receptor tyrosine kinase
  • BCR activator of RhoGEF and GTPase
  • chromosome rearrangement
  • chromosome translocation
  • leukemia
  • oncogene
  • Philadelphia chromosome
  • protein chimera
  • protein degradation
  • proteolysis
  • SMAD-specific E3 ubiquitin protein ligase 1 (Smurf1)
  • ubiquitin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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