Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking.
Reads0
Chats0
TLDR
It is concluded that the association of the EGFR with different proteins is compartment specific and ligand loss is the proximal cause of EGFR inactivation, and regulated trafficking could potentially influence the pattern as well as the duration of signal transduction.Abstract:
Ligand activation of the epidermal growth factor receptor (EGFR) leads to its rapid internalization and eventual delivery to lysosomes. This process is thought to be a mechanism to attenuate signaling, but signals could potentially be generated after endocytosis. To directly evaluate EGFR signaling during receptor trafficking, we developed a technique to rapidly and selectively isolate internalized EGFR and associated molecules with the use of reversibly biotinylated anti-EGFR antibodies. In addition, we developed antibodies specific to tyrosine-phosphorylated EGFR. With the use of a combination of fluorescence imaging and affinity precipitation approaches, we evaluated the state of EGFR activation and substrate association during trafficking in epithelial cells. We found that after internalization, EGFR remained active in the early endosomes. However, receptors were inactivated before degradation, apparently due to ligand removal from endosomes. Adapter molecules, such as Shc, were associated with EGFR both at the cell surface and within endosomes. Some molecules, such as Grb2, were primarily found associated with surface EGFR, whereas others, such as Eps8, were found only with intracellular receptors. During the inactivation phase, c-Cbl became EGFR associated, consistent with its postulated role in receptor attenuation. We conclude that the association of the EGFR with different proteins is compartment specific. In addition, ligand loss is the proximal cause of EGFR inactivation. Thus, regulated trafficking could potentially influence the pattern as well as the duration of signal transduction.read more
Citations
More filters
Journal ArticleDOI
Signals for Sorting of Transmembrane Proteins to Endosomes and Lysosomes
TL;DR: This work has shown that peptide motifs serve as a signal for sorting at various stages of the endosomal-lysosomal system and several proteins, including clathrin, AP-2, and Dab2, have been proposed to function as recognition proteins for NPXY signals.
Journal ArticleDOI
Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors.
Birgit Schoeberl,Claudia Eichler-Jonsson,Ernst Dieter Gilles,Ernst Dieter Gilles,Gertraud Müller +4 more
TL;DR: The model provides insight into signal–response relationships between the binding of EGF to its receptor at the cell surface and the activation of downstream proteins in the signaling cascade, showing that EGF-induced responses are remarkably stable over a 100-fold range of ligand concentration.
Journal ArticleDOI
Signal transduction and endocytosis: close encounters of many kinds.
TL;DR: Recent studies of protein tyrosine kinases and G-protein-coupled receptors have shed new light on the mechanisms and functional consequences of this bidirectional interplay between signalling and membrane-transport networks.
Journal ArticleDOI
Ras proteins: different signals from different locations
TL;DR: Recent studies have shown that Ras proteins interact dynamically with specific microdomains of the plasma membrane as well as with other internal cell membranes, highlighting the complex interplay between Ras location and function.
Journal ArticleDOI
A quantitative protein interaction network for the ErbB receptors using protein microarrays
TL;DR: The extent to which promiscuity changes with protein concentration may contribute to the oncogenic potential of receptor tyrosine kinases, and perhaps other signalling proteins as well.
References
More filters
Journal ArticleDOI
Targeted Disruption of Mouse EGF Receptor: Effect of Genetic Background on Mutant Phenotype
David W. Threadgill,Andrzej A. Dlugosz,Laura A. Hansen,Tamar Tennenbaum,Ulrike Lichti,Della Yee,Christian LaMantia,Tracy Mourton,Karl Herrup,Raymond C. Harris,John A. Barnard,Stuart H. Yuspa,Robert J. Coffey,Terry Magnuson +13 more
TL;DR: The multiple abnormalities associated with EGFR deficiency indicate that the receptor is involved in a wide range of cellular activities.
Journal ArticleDOI
Receptor protein-tyrosine kinases and their signal transduction pathways
Journal ArticleDOI
The Tyrosine Kinase Negative Regulator c-Cbl as a RING-Type, E2-Dependent Ubiquitin-Protein Ligase
Claudio A. P. Joazeiro,Simon S. Wing,Han-kuei Huang,Joel D. Leverson,Tony Hunter,Yun-Cai Liu +5 more
TL;DR: The c-Cbl protein acted as an E3 that can recognize tyrosine-phosphorylated substrates, such as the activated platelet-derived growth factor receptor, through its SH2 domain and that recruits and allosterically activates an E2 ubiquitin-conjugating enzyme through its RING domain.
Journal ArticleDOI
Control of EGF receptor signaling by clathrin-mediated endocytosis.
TL;DR: Endocytic trafficking of activated EGFR plays a critical role not only in attenuating EGFR signaling but also in establishing and controlling specific signaling pathways.
Journal ArticleDOI
Strain-dependent epithelial defects in mice lacking the EGF receptor
Maria Sibilia,Erwin F. Wagner +1 more
TL;DR: Results indicate that the EGFR regulates epithelial proliferation and differentiation and that the genetic background influences the resulting phenotype.