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SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry
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Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl)

Shan Zeng1, Zhiheng Xu, Stan Lipkowitz

  • 1Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Blood
|August 19, 2004
PubMed

Insights

Stem cell factor (SCF) activates KIT receptor tyrosine kinase, leading to Cbl protein interaction and degradation. This establishes a negative feedback loop, down-regulating KIT signaling in various human diseases.

Area of Science:

  • Cellular signaling pathways
  • Molecular mechanisms of disease
  • Protein ubiquitination and degradation

Background:

  • The KIT receptor tyrosine kinase plays a role in several human diseases.
  • Mechanisms regulating KIT signaling are not fully understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of KIT signaling.
  • To investigate the role of Cbl proteins in KIT regulation.

Main Methods:

  • Studied the interaction between KIT and Cbl proteins upon stem cell factor (SCF) stimulation.
  • Investigated the role of Cbl protein domains in ubiquitination and degradation.

Main Results:

  • SCF stimulation induces KIT and Cbl protein interaction and mutual degradation.
  • Activated KIT phosphorylates Cbl proteins, which then mediate KIT ubiquitination and degradation.
  • Tyrosine kinase binding and RING finger domains of Cbl are crucial for KIT degradation.

Conclusions:

  • A negative feedback loop regulates SCF-KIT signaling.
  • Activated KIT induces Cbl activation, leading to KIT degradation and signaling down-regulation.

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