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RING finger mutations that abolish c-Cbl-directed polyubiquitination and downregulation of the EGF receptor are

C B Thien1, F Walker, W Y Langdon

  • 1Department of Pathology, University of Western Australia, Western Australia 6009, Crawley, Australia.

Molecular Cell
|March 10, 2001
PubMed

Insights

Mutations in the c-Cbl protooncogene

Area of Science:

  • Oncogenic signaling pathways
  • Protein ubiquitination and degradation

Background:

  • The c-Cbl protooncogene acts as a negative regulator of receptor protein tyrosine kinases (RPTKs).
  • c-Cbl targets activated RPTKs for polyubiquitination and downregulation, a process requiring its tyrosine kinase binding (TKB) and RING finger domains.
  • Oncogenic Cbl proteins are hypothesized to function in a dominant-negative manner, inhibiting wild-type c-Cbl activity.

Purpose of the Study:

  • To investigate the role of specific c-Cbl domains in RPTK regulation and oncogenic transformation.
  • To test the hypothesis that oncogenic Cbl proteins inhibit wild-type c-Cbl function through a dominant-negative mechanism.

Main Methods:

  • Site-directed mutagenesis of the c-Cbl RING finger domain and the alpha-helical region.
  • Assessment of c-Cbl-directed polyubiquitination and downregulation of RPTKs.
  • Evaluation of Cbl protein oncogenic transformation potential in cellular assays.

Main Results:

  • Mutations in the RING finger domain abolished c-Cbl-mediated polyubiquitination and downregulation of RPTKs.
  • These RING finger mutations did not induce cellular transformation.
  • Mutations within a conserved alpha-helical structure, distinct from the RING finger, rendered Cbl proteins oncogenic.

Conclusions:

  • Cbl-mediated oncogenic transformation involves mechanisms beyond the polyubiquitination and downregulation of RPTKs.
  • The RING finger domain and its E2 ubiquitin-conjugating enzyme recruitment function are not essential for Cbl-induced transformation.
  • Specific mutations in the alpha-helical region linking the SH2 and RING finger domains are critical for Cbl oncogenic activity.

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