Systems biology of growth factor-induced receptor endocytosis.
Clathrin-mediated endocytosis sorts for degradation of more than 50 different growth factor receptors capable of relaying growth and differentiation signals by means of their cytoplasm-facing, intrinsic tyrosine kinase activity. The kinetics and alternative routings of receptor endocytosis critically regulate growth factor signaling, which underscores the importance of understanding mechanisms underlying fail-safe operation (robustness) and fidelity of the pathway. Like other robust systems, a layered hub-centric network controls receptor endocytosis. Characteristically, the modular hubs (e.g., AP2-Eps15 and Hrs) contain a membrane-anchoring lipid-binding domain, an ubiquitin-binding module, which recruits ubiquitinylated cargo, and a machinery enabling homo-assembly. Scheduled hub transitions, as well as cascades of Rab family guanosine triphosphatases and membrane bending machineries, define points of commitment to vesicle budding, thereby securing unidirectional trafficking. System's bistability permits stimulation by a growth factor, which oscillates a series of switches based on posttranslational protein modifications (i.e., phosphorylation, ubiquitinylation and neddylation), as well as transient low-affinity/high-avidity protein assemblies. Cbl family ubiquitin ligases, along with a set of phosphotyrosine-binding adaptors (e.g., Grb2), integrate receptor endocytosis into the densely wired networks of signal transduction pathways, which are involved in health and disease.
Zwang
Yaara
Y
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Yarden
Yosef
Y
D000199:Actins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D002966:Clathrin; D036341:Intercellular Signaling Peptides and Proteins; D017978:Receptors, Growth Factor; D044767:Ubiquitin-Protein Ligases; D020794:Receptor Protein-Tyrosine Kinases; D020558:GTP Phosphohydrolases; D020691:rab GTP-Binding Proteins