Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl).
Activation of the KIT receptor tyrosine kinase contributes to the pathogenesis of several human diseases, but the mechanisms regulating KIT signaling have not been fully characterized. Here, we show that stem cell factor (SCF), the ligand for KIT, induces the interaction between KIT and Cbl proteins and their mutual degradation. Upon SCF stimulation, KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. We propose a negative feedback loop controlling the SCF-KIT signaling pathway, in which SCF activates KIT. The activated KIT in turn induces phosphorylation and activation of Cbl proteins. The Cbl proteins then bind and direct the degradation of activated KIT, leading to down-regulation of KIT signaling.
Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Shan
S
Zeng
Zhiheng
Z
Xu
Stan
S
Lipkowitz
Jack B
JB
Longley
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D011518:Proto-Oncogene Proteins; D019089:Stem Cell Factor; D025801:Ubiquitin; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019009:Proto-Oncogene Proteins c-kit; C493849:Cbl protein, mouse