rab7 activity affects epidermal growth factor:epidermal growth factor receptor degradation by regulating endocytic trafficking from the late endosome.
The epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine kinase family. Ligand (epidermal growth factor or EGF) binding to the EGFR results in the coordinated activation and integration of biochemical signaling events to mediate cell growth, migration, and differentiation. One mechanism the cell utilizes to orchestrate these events is ligand-mediated endocytosis through the canonical clathrin-mediated endocytic pathway. Identification of proteins that regulate the intracellular movement of the EGF.EGFR complex is an important first step in dissecting how specificity of EGFR signaling is conferred. We examined the role of the small molecular weight guanine nucleotide-binding protein (G-protein) rab7 as a regulator of the distal stages of the endocytic pathway. Through the transient expression of activating and inactivating mutants of rab7 in HeLa cells, we have determined that rab7 activity directly correlates with the rate of radiolabeled EGF and EGFR degradation. Furthermore, when inhibitory mutants of rab7 are expressed, the internalized EGF.EGFR complex accumulates in high-density endosomes that are characteristic of the late endocytic pathway. Thus, we conclude that rab7 regulates the endocytic trafficking of the EGF.EGFR complex by regulating its lysosomal degradation.
Ceresa
Brian P
BP
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, 73190, USA. brian-ceresa@ouhsc.edu
Bahr
Steven J
SJ
D000256:Adenoviridae / Q000235:genetics; D045744:Cell Line, Tumor; D002468:Cell Physiological Phenomena; D002966:Clathrin / Q000737:chemistry; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D005799:Genes, Dominant; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D013997:Time Factors; D020691:rab GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D000090802:rab7 GTP-Binding Proteins
D002966:Clathrin; D008024:Ligands; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020691:rab GTP-Binding Proteins