EGF receptor downregulation depends on a trafficking motif in the distal tyrosine kinase domain.
On binding to its receptor, epidermal growth factor (EGF) initiates a cascade of events leading to cell proliferation or differentiation. In addition, the EGF receptor itself is downregulated to attenuate mitogenic signaling. Downregulation occurs through trafficking of receptors to lysosomes, culminating in proteolytic destruction of both the receptor and ligand; however, endocytic sorting mechanisms that underlie lysosomal targeting remain obscure. The goal of this study was to explore one aspect of the molecular basis for ligand-induced lysosomal targeting and degradation of EGF receptors. In this study, we identify a tyrosine-leucine motif ((954)YLVI) that is essential for transit of ligand-receptor complexes to lysosomes. When this motif is mutated, HEK 293 cells expressing the mutant receptors demonstrate impaired lysosomal targeting and downregulation compared with wild-type receptors. (954)YLVI is highly conserved among EGF receptors from various mammalian and invertebrate species and is critical for receptor downregulation. We propose that (954)YLVI works in concert with at least two additional regions within the EGF receptor cytoplasmic domain that are essential for efficiently targeting ligand-receptor complexes to the lysosome.
Jones
Stacie M
SM
Department of Pediatrics, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA.
Foreman
Susan K
SK
Shank
Brian B
BB
Kurten
Richard C
RC
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D021382:Protein Sorting Signals; D021381:Protein Transport / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*
D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors