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Am J Physiol Cell Physiol 282: C420-C433, 2002. First published October 31, 2001; doi:10.1152/ajpcell.00253.2001
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Vol. 282, Issue 3, C420-C433, March 2002

EGF receptor downregulation depends on a trafficking motif in the distal tyrosine kinase domain

Stacie M. Jones1,2, Susan K. Foreman1, Brian B. Shank2, and Richard C. Kurten2

Departments of 1 Pediatrics and 2 Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

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 (954YLVI) 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. 954YLVI is highly conserved among EGF receptors from various mammalian and invertebrate species and is critical for receptor downregulation. We propose that 954YLVI 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.

degradation; lysosomes; ubiquitination; targeting


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