c-Cbl is a critical modulator of the Ron tyrosine kinase receptor

Ron, the receptor tyrosine kinase (RTK) for the macrophage stimulating protein (MSP), activates multiple signaling pathways by recruiting several positive regulators to a multifunctional docking site. Here we show that stimulation by MSP also recruits a negative regulator, the c-Cbl ubiquitin ligase...

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Veröffentlicht in:Oncogene Jg. 22; H. 24; S. 3669 - 3679
Hauptverfasser: Penengo, Lorenza, Rubin, Chanan, Yarden, Yosef, Gaudino, Giovanni
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 12.06.2003
Nature Publishing
Nature Publishing Group
Schlagworte:
Adaptor Proteins, Signal Transducing
Apoptosis
Biological and medical sciences
Cbl protein
Cell Biology
Cell physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Endocytosis
Fundamental and applied biological sciences. Psychology
GRB2 Adaptor Protein
Grb2 protein
Growth factors
Human Genetics
Humans
Internal Medicine
Kinases
Ligands
Macrophages
Medicine
Medicine & Public Health
Molecular and cellular biology
MSP protein
Oncology
original-paper
Phosphotyrosine
Protein-tyrosine kinase receptors
Proteins
Proteins - physiology
Proto-Oncogene Proteins - chemistry
Proto-Oncogene Proteins - physiology
Proto-Oncogene Proteins c-cbl
Receptor Protein-Tyrosine Kinases - metabolism
Receptors, Cell Surface - metabolism
src Homology Domains
Tumorigenesis
Ubiquitin
Ubiquitin - metabolism
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases
Ron
Grb2
c-Cbl
ubiquitylation
c-Cb1
Enzyme
Kinase
Transferases
Biological receptor
ISSN:0950-9232, 1476-5594
Online-Zugang:Volltext
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Beschreibung
Zusammenfassung:Ron, the receptor tyrosine kinase (RTK) for the macrophage stimulating protein (MSP), activates multiple signaling pathways by recruiting several positive regulators to a multifunctional docking site. Here we show that stimulation by MSP also recruits a negative regulator, the c-Cbl ubiquitin ligase, to the multifunctional docking site as well as to a juxtamembrane tyrosine autophosphorylation site. c-Cbl recruitment to these two sites results in polyubiquitylation of Ron molecules, which are subsequently sorted for endocytosis and degradation. Both the phosphotyrosine binding domain of c-Cbl and its RING domain are essential for downregulation of Ron. Although Ron and c-Cbl are found also in physical complexes that include Grb2, these associations are insufficient for productive ubiquitylation of Ron. Our results shed light on the mechanism of receptor desensitization mediated by c-Cbl and its binding partner Grb2.
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ISSN:0950-9232
1476-5594
DOI:10.1038/sj.onc.1206585