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Csk homologous kinase (CHK) and ErbB-2 interactions are directly coupled with CHK negative growth regulatory function

Soyoun Kim1, Radoslaw Zagozdzon, Alan Meisler

  • 1Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.

The Journal of Biological Chemistry
|July 18, 2002
PubMed

Insights

Csk homologous kinase (CHK) specifically binds ErbB-2, inhibiting Src kinase activity and breast cancer growth. Mutants altering this binding confirm CHK

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Csk homologous kinase (CHK) negatively regulates human breast cancer growth.
  • CHK inhibits ErbB-2/neu-mediated Src family kinase activity.
  • The CHK SH2 domain interaction with Tyr(P)(1248) of ErbB-2 is critical for CHK function.

Purpose of the Study:

  • To investigate the direct relationship between CHK SH2 domain binding to ErbB-2 and the inhibition of heregulin-stimulated Src kinase activity.
  • To characterize CHK SH2 domain binding mutants for their interaction with ErbB-2.

Main Methods:

  • Construction and analysis of three CHK SH2 domain binding mutants (G129R, R147K, R147A).
  • Nuclear Magnetic Resonance (NMR) spectroscopy to evaluate mutant binding to a Tyr(P)(1248)-containing ErbB-2 peptide.
  • Assessment of heregulin-stimulated Src kinase activity inhibition by CHK mutants.

Main Results:

  • The G129R mutant showed enhanced binding to ErbB-2, similar to wild-type CHK.
  • The R147A mutant completely disrupted CHK SH2 domain binding to ErbB-2.
  • Enhanced CHK binding (G129R) strengthened Src kinase inhibition, while disrupted binding (R147A) diminished inhibition.

Conclusions:

  • The specific interaction between the CHK SH2 domain and ErbB-2 is directly responsible for CHK's growth inhibitory effects.
  • High-affinity CHK binding constructs may be valuable for targeting the ErbB-2/Src pathway in breast cancer gene therapy.

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