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Articles in PresS, published online ahead of print October 31, 2001
Am J Physiol Cell Physiol, 10.1152/ajpcell.00253.2001
Submitted on June 6, 2001
Accepted on October 24, 2001
1 Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
2 Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
3 Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
* To whom correspondence should be addressed. E-mail: JonesStacieM{at}uams.edu.
Upon binding to its receptor, EGF initiates a cascade of events leading to cell proliferation or differentiation. In addition, the EGF receptor itself is down-regulated to attenuate mitogenic signaling. Down-regulation 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 down-regulation when compared to wild-type receptors. 954YLVI is highly conserved among EGF receptors from various mammalian and invertebrate species and is critical for receptor down-regulation. 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.
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