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, 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.
Penengo
Lorenza
L
Department of Medical Sciences, University of Piemonte Orientale, Novara 28100, Italy.
Rubin
Chanan
C
Yarden
Yosef
Y
Gaudino
Giovanni
G
D048868:Adaptor Proteins, Signal Transducing; D004705:Endocytosis; D051380:GRB2 Adaptor Protein; D006801:Humans; D011506:Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D025801:Ubiquitin; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C067419:CBL protein, human