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Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta
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The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase

C A Joazeiro1, S S Wing, H Huang

  • 1The Salk Institute, Molecular Biology and Virology Laboratory, La Jolla, CA 92037, USA.

Science (New York, N.Y.)
|October 9, 1999
PubMed

Insights

The c-Cbl protein acts as a ubiquitin-protein ligase, targeting receptor protein-tyrosine kinases (RPTKs) for degradation. This discovery reveals a new mechanism for controlling cell signaling pathways.

Area of Science:

  • Cellular signaling
  • Protein ubiquitination
  • Molecular biology

Background:

  • Receptor protein-tyrosine kinases (RPTKs) signal termination involves ubiquitination and degradation.
  • The c-Cbl adapter protein influences RPTK ubiquitination via its SH2 and RING domains.

Purpose of the Study:

  • To elucidate the role of c-Cbl in RPTK signaling termination.
  • To determine how c-Cbl functions as a ubiquitin-protein ligase.

Main Methods:

  • Investigating the interaction between c-Cbl, RPTKs, and ubiquitin-conjugating enzymes.
  • Analyzing the functional domains of c-Cbl (SH2 and RING) in the ubiquitination process.

Main Results:

  • c-Cbl functions as a ubiquitin-protein ligase (E3).
  • The SH2 domain of c-Cbl recognizes tyrosine-phosphorylated substrates like activated platelet-derived growth factor receptor.
  • The RING domain of c-Cbl recruits and activates E2 ubiquitin-conjugating enzymes.

Conclusions:

  • c-Cbl provides a distinct mechanism for substrate targeting in the ubiquitin system.
  • This finding expands our understanding of how ubiquitination regulates RPTK signaling.

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