Abstract
Growth factors and their transmembrane receptor tyrosine kinases play pivotal roles in morphogenesis, cell fate determination and pathogenesis, including multiple stages of cancer. The amplitude and kinetics of signaling by growth factor receptors are determined by an endocytic process, which sorts activated, autophosphorylated receptors to degradation in lysosomes. Recent studies uncovered the role of protein ubiquitylation in vesicular trafficking of growth factor receptors. Decoration of ligand-activated receptors by multiple monomeric ubiquitins distinguishes this degradative route from the proteasome-mediated pathway, which involves polymeric chains of ubiquitin. Although receptor ubiquitylation occurs at the cell surface, its major role is to sort internalized receptors to the lumen of the multivesicular body, en route to the lysosome. The ubiquitin ligases that control this late sorting event belong to the Cbl family of RING finger adaptors, which bind specific phosphotyrosine residues in the receptors upon activation by ligand. Another group of E3 ubiquitin ligases, the Nedd4 family, regulates the initial sorting event, which targets receptors to clathrin-coated regions of the plasma membrane. This step entails ubiquitin-dependent assembly of a clathrin-binding complex of adaptors such as epsins, which share ubiquitin-interacting motifs. The concerted action of both ubiquitin-binding adaptors of membrane coats and E3 ligases, as well as their regulation by protein phosphorylation and ubiquitylation, ensure robust endocytosis of growth factor receptors. Genetic defects and virus-mediated manipulations of the endocytic pathway divert receptors to a default recycling pathway, thereby enabling unrestrained signaling characteristic to transformed cells.
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Acknowledgements
We thank our group members for insightful feedback. MM is supported by an EMBO long-term fellowship. YY is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our laboratory is supported by research grants from Willner Center for Vascular Biology, the Israel Academy of Sciences and Humanities, the National Cancer Institute (Grant CA72981), The Israel Science Foundation, CapCURE, and the US Army (Grant DAMD 17-00-1-0499).
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Marmor, M., Yarden, Y. Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene 23, 2057–2070 (2004). https://doi.org/10.1038/sj.onc.1207390
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