RAB7 and TSG101 are required for the constitutive recycling of unliganded EGFRs via distinct mechanisms.
Both constitutive and ligand-mediated membrane trafficking regulate Epidermal Growth Factor Receptor (EGFR) signaling. The constitutive endocytosis and recycling of the unliganded EGFR is a critical determinant of cell surface EGFR expression and the cell's sensitivity to ligands. We report that two proteins with established roles in trafficking the EGF:EGFR complex to the lysosome also regulate the recycling of the unliganded EGFR. Knock down of either Tumor suppressor gene 101 (TSG101) or RAB7 causes the endosomal accumulation of the inactive, unliganded receptor in morphologically and biochemically distinct organelles. Knock down of TSG101 causes the EGFR to accumulate in low density endosomes whereas RAB7 knock down results in EGFR accumulation in high density endosomes. Knock down of either protein caused the receptor to co-localize primarily with LAMP-1, but not EEA1. These two proteins regulate EGFR slow, perinuclear recycling, via distinct mechanism and are new molecular targets that regulate cell surface EGFR expression.
Department of Pharmacology and Toxicology, University of Louisville, United States.
Jamie S
JS
Rush
Brian P
BP
Ceresa
D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D011992:Endosomes; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D021381:Protein Transport; D011990:Receptors, Transferrin / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins; D000099177:Tsg101 Protein
D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D066246:ErbB Receptors; D011990:Receptors, Transferrin; D014157:Transcription Factors; D020691:rab GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; D000099177:Tsg101 Protein; C000716463:rab7 GTP-binding proteins, human; C512478:EGFR protein, human
Control siRNA; EEA1; EGF; EGFR; ESCRT; Early Endosome Autoantigen 1; Endocytosis; Endosomal sorting complex required for transport; Epidermal Growth Factor; Epidermal Growth Factor Receptor; G-protein; Guanosine nucleotide binding protein; LAMP-1/2; LE/MVB; Late endosome; Late endosome/multivesicular body; Lysosome Associated Membrane Protein-1/2; RAB7; Recycling endosome; TSG101; TfnR; Tumor suppressor gene 101; siCON; transferrin receptor