Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptorubiquitylation

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 ulti- mately 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.

The key roles of cancer stem cell-derived extracellular vesicles

Cancer stem cells(CSCs),the subpopulation of cancer cells,have the capability of proliferation,self-renewal,and differentiation.The presence of CSCs is a key factor leading to tumor progression and metastasis.Extracellular vesicles(EVs)are nano-sized particles released by different kinds of cells and have the capacity to deliver certain cargoes,such as nucleic acids,proteins,and lipids,which have been recognized as a vital mediator in cell-to-cell communication.Recently,more and more studies have reported that EVs shed by CSCs make a significant contribution to tumor progression.CSCs-derived EVs are involved in tumor resistance,metastasis,angiogenesis,as well as the maintenance of sternness phenotype and tumor immunosuppression microenvironment.Here,we summarized the molecular mechanism by which CSCs-derived EVs in tumor progression.We believed that the fully understanding of the roles of CSCs-derived EVs in tumor development will definitely provide new ideas for CSCs-based therapeutic strategies.