Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation.
Intracellular signals mediated by the family of receptor tyrosine kinases play pivotal roles in morphogenesis, cell fate determination and pathogenesis. Precise control of signal amplitude and duration is critical for the fidelity and robustness of these processes. Activation of receptor tyrosine kinases by their cognate growth factors not only leads to propagation of the signal through various biochemical cascades, but also sets in motion multiple attenuation mechanisms that ultimately terminate the active state. Early attenuators pre-exist prior to receptor activation and they act to limit signal propagation. Subsequently, late attenuators, such as Lrig and Sprouty, are transcriptionally induced and further act to dampen the signal. Central to the process of signaling attenuation is the role of the E3 ubiquitin ligase c-Cbl. While Cbl-mediated processes of receptor ubiquitylation and endocytosis are relatively well understood, the links of Cbl to other negative regulators are just now beginning to be appreciated. Here we review some emerging interfaces between Cbl and the transcriptionally induced negative regulators Lrig and Sprouty.
Rubin
Chanan
C
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Gur
Gal
G
Yarden
Yosef
Y
D000818:Animals; D015536:Down-Regulation; D004705:Endocytosis; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D006133:Growth Substances; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D020794:Receptor Protein-Tyrosine Kinases