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(Received for publication, July 18, 1996, and in revised form, September 19, 1996)
From the Binding of epidermal growth factor (EGF) to its
receptor induces rapid internalization and degradation of both ligand
and receptor via the lysosomal pathway. To study the mechanism of intracellular sorting of EGF-EGF receptor complexes to lysosomes, NIH
3T3 cells transfected with wild-type and mutant EGF receptors were
employed. The kinetics of 125I-EGF trafficking was analyzed
using low concentrations of the ligand to avoid saturation of the
specific sorting system. The relative size of the pool of internalized
125I-EGF-receptor complexes that were capable of recycling
decreased as receptors traversed the endosomal system. The rate of
125I-EGF sequestration from the recycling pathway
correlated with the rate of 125I-EGF transition from early
to late endosomes as measured by Percoll gradient fractionation.
Deletion of the last 63 amino acids of the EGF receptor cytoplasmic
tail did not inhibit the process of sequestration and targeting to the
late endosomes and lysosomes. Truncation of the 123 residues, however,
resulted in impaired lysosomal targeting and increased recycling of
EGF. Receptor mutant in which 165 residues were deleted displayed
maximal ability to recycle and a minimal extent of sorting to the late
endosomes. The data suggest that two regions of the EGF receptor
molecule, residues 1022-1063 and to a lesser extent residues
1063-1123, contribute in the regulation of routing of EGF receptors to
the degradation pathway. The kinase-negative receptor mutant
recycled EGF more intensively compared with the wild-type receptor, and the transport of this mutant to late endosomes was inhibited. These
results support the view that the receptor kinase activity is important
for ligand-induced sorting of EGF receptors to the pathway of lysosomal
degradation.
Volume 271, Number 48,
Issue of November 29, 1996
pp. 30340-30346
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
§
,
,
and
Department of Pharmacology and
Cancer Center, University of Colorado
Health Sciences Center, Denver, Colorado 80262, the
§ Institute of Cytology, Russian Academy of Science,
Tikhoretsky 4, St. Petersburg, 194064 Russia, and 
Laboratorio di
Oncologia Molecolare, DIBIT and Instituto di Neuroscienze e Biommagini
del Consiglio Nazionale delle Ricerche, H. S. Raffaele,
Milano, 20132 Italy
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