Endosomes, receptor tyrosine kinase internalization and signal transduction

Abstract

Upon the binding of insulin or epidermal growth factor to their cognate receptors on the liver parenchymal plasmalemma, signal transduction and receptor internalization are near co-incident. Indeed, the rapidity and extent of ligand mediated receptor internalization into endosomes in liver as well as other organs predicts that signal transduction is regulated at this intracellular locus. Although internalization has been thought as a mechanism to attenuate ligand mediated signal transduction responses, detailed studies of internalized receptors in isolated liver endosomes suggest an alternative scenario whereby selective signal transduction pathways can be accessed at this locus.

A chimeric fusion protein containing transforming growth factor-α mediates gene transfer via binding to the EGF receptor

“…This initiates the signal transduction cascade and also results in the recruitment of the EGF receptor to clathrincoated pits which is followed by internalization of the ligand-receptor complex along the endocytic pathway. 17 To determine whether binding of TEG to the EGF receptor induces a response similar to that initiated by natural ligands, the ability of TEG to activate EGF receptor was tested. COS-1 and A431 cells were treated for 10 min at 37°C with the fusion protein in the presence or absence of the antagonistic EGF-receptor specific MAb 14E1 16 as a competitor.…”

“…Binding of growth factors to the EGF receptor triggers receptor dimerization followed by receptor activation and internalization of the ligand-receptor complex along the endocytic pathway, thereby initiation of signal transduction and internalization of the EGF receptor coincide. 17 TGF-␣ is depleted from the medium at a faster rate than EGF 26 and might therefore be a better candidate as a ligand for targeted gene delivery. Since the TEG fusion protein like natural growth factors induces autophosphorylation of the EGF receptor it is very likely that it also triggers rapid internalization.…”

Superagonistic activation of ErbB-1 by EGF-related growth factors with enhanced association and dissociation rate constants

“…However, recent data show that the ErbB-1 receptor is not only active at the cell surface but may still be actively signaling during internalization of the receptor-ligand complex (6,7). As a consequence 4 thereof, the fate of the internalized receptor may have direct consequences for the intensity of the growth factor-induced biological signal.…”

Extracellular Matrix Proteins Modulate Endocytosis of the Insulin Receptor

“…The internalized receptor undergoes sorting, which determines whether it will be subjected to degradation in lysosomes or whether it will recycle back to the plane of the membrane (7). Stimulation of the intrinsic Tyr kinase activity of the insulin receptor (IR) 1 following insulin binding is a prerequisite for surface redistribution of receptor-insulin complexes; accordingly, mutations of IR that abolish its kinase activity or mutations that replace amino acids that constitute putative "internalization signal" motifs inhibit IR internalization (8 -13).…”

“…Internalized receptors are then sorted to distinct subcellular pathways that lead either to degradation or recycling to the cell surface (1)(2)(3). Similarly, internalization of the insulin receptor is a multi-step process (4).…”