Abstract
The mammalian tumor susceptibility gene tsg101 encodes the homologue of Vps23p, a class E Vps protein essential for normal membrane trafficking in the late endosome/multivesicular body of yeast. Both proteins assemble into large (approximately 350 kDa) cytosolic protein complexes and we show that the yeast complex contains another class E Vps protein, Vps28p. tsg101 mutant cells exhibit defects in sorting and proteolytic maturation of the lysosomal hydrolase cathepsin D, as well as in the steady-state distribution of the mannose-6-phosphate receptor. Additionally, endocytosed EGF receptors that are normally sorted to the lysosome are instead rapidly recycled back to the cell surface in tsg101 mutant cells. We propose that tsg101 mutant cells are defective in the delivery of cargo proteins to late endosomal compartments. One consequence of this endosomal trafficking defect is the delayed down-regulation/degradation of activated cell surface receptors, resulting in prolonged signaling. This may contribute to the tumorigenic phenotype exhibited by the tsg101 mutant fibroblasts.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells / metabolism
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Amino Acid Sequence
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Animals
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Carrier Proteins / physiology*
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Cathepsin D / metabolism
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Endocytosis / physiology*
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Endosomal Sorting Complexes Required for Transport
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Endosomes / metabolism*
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ErbB Receptors / metabolism
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Fungal Proteins / chemistry
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Fungal Proteins / genetics
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Fungal Proteins / physiology*
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Lysosomes / metabolism
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MAP Kinase Signaling System
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Macromolecular Substances
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Mice
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Molecular Sequence Data
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Protein Transport
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor, IGF Type 2 / metabolism
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Receptors, Transferrin / metabolism
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Recombinant Fusion Proteins / metabolism
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism
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Saccharomyces cerevisiae Proteins*
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Sequence Alignment
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Sequence Homology, Amino Acid
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Vesicular Transport Proteins*
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Endosomal Sorting Complexes Required for Transport
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Fungal Proteins
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Macromolecular Substances
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Receptor, IGF Type 2
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Receptors, Transferrin
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Recombinant Fusion Proteins
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STP22 protein, S cerevisiae
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Saccharomyces cerevisiae Proteins
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Transcription Factors
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Tsg101 protein
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VPS28 protein, S cerevisiae
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Vesicular Transport Proteins
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ErbB Receptors
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Receptor Protein-Tyrosine Kinases
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Cathepsin D