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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Vydáno v:	Oncogene Ročník 22; číslo 24; s. 3669 - 3679
Hlavní autoři:	Penengo, Lorenza, Rubin, Chanan, Yarden, Yosef, Gaudino, Giovanni
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 12.06.2003 Nature Publishing Nature Publishing Group
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/sj.onc.1206585