Regulating the regulator: negative regulation of Cbl ubiquitin ligases

Trends Biochem Sci. 2006 Feb;31(2):79-88. doi: 10.1016/j.tibs.2005.12.004. Epub 2006 Jan 6.


Cbl proteins are regulators of signal transduction through many pathways and, consequently, regulate cell function and development. They are ubiquitin ligases that ubiquitinate and target many signaling molecules for degradation. The Cbl proteins themselves are regulated by an increasingly complex network of interactions that fine-tune the effects that Cbl proteins have on signaling. The negative regulation of Cbl protein function can occur via cis-acting structural elements that prevent inappropriate ubiquitin ligase activity, degradation of the Cbl proteins, inhibition without degradation owing to interaction with other signaling proteins, deubiquitination of Cbl substrates, and regulation of assembly of the endosomal ESCRT-I complex. Defects in the regulatory mechanisms that control Cbl function are implicated in the development of immunological and malignant diseases.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Animals
  • Autoimmune Diseases / physiopathology
  • CD28 Antigens / metabolism
  • Calcium-Binding Proteins / physiology
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology
  • Cell Cycle Proteins / physiology
  • Cortactin / physiology
  • Endosomal Sorting Complexes Required for Transport
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Membrane Proteins
  • Neoplasms / physiopathology
  • Nerve Tissue Proteins / physiology
  • Oncogene Proteins, Viral / physiology
  • Protein Tyrosine Phosphatases
  • Proto-Oncogene Proteins c-cbl / genetics*
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Proto-Oncogene Proteins c-kit / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Ubiquitin-Protein Ligases / metabolism
  • cdc42 GTP-Binding Protein / physiology
  • src-Family Kinases / metabolism


  • CD28 Antigens
  • CLIP4 protein, human
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cortactin
  • Endosomal Sorting Complexes Required for Transport
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Oncogene Proteins, Viral
  • PDCD6IP protein, human
  • Spry2 protein, rat
  • oncogene protein E5, Human papillomavirus type 16
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Proto-Oncogene Proteins c-kit
  • src-Family Kinases
  • Protein Tyrosine Phosphatases
  • UBASH3B protein, human
  • cdc42 GTP-Binding Protein