Continual expression of Rab5(Q79L) causes a ligand-independent EGFR internalization and diminishes EGFR activity.
The amount of cell-surface Epidermal Growth Factor Receptor (EGFR) available to secreted ligand (EGF) dictates a cell's ability to mediate cell proliferation, differentiation or migration. Multiple factors regulate EGFR cell-surface expression including the rates of protein synthesis and protein degradation, and the endocytic trafficking of both stimulated and unstimulated EGFR. Rab5 is a 25 kDa protein that is localized to the plasma membrane and the early endosome. Its exact molecular function, however, remains controversial. We have used stable and transient expression systems in HeLa cells to examine the consequence of continual, overexpression of wild-type and activated mutants of rab5 on EGFR localization and signaling. Continual expression of constitutively activated mutants of rab5 causes a ligand-independent redistribution of EGFRs into intracellular vesicles that can not be blocked with an antagonistic antibody. The net result is a decrease in the level of cell-surface EGFRs available for ligand stimulation. Thus, rab5 activation regulates EGFR signaling by facilitating the internalization of the unliganded EGFR.
Dinneen
Jennifer L
JL
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA.
Ceresa
Brian P
BP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D004285:Dogs; D004705:Endocytosis / Q000502:physiology*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D008024:Ligands; D009154:Mutation; D011869:Radioligand Assay; D015398:Signal Transduction / Q000502:physiology; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes; D008024:Ligands; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020696:rab5 GTP-Binding Proteins