Mammalian tumor susceptibility gene 101 (TSG101) and the yeast homologue, Vps23p, both function in late endosomal trafficking.
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.
Babst
M
M
Division of Cellular and Molecular Medicine and Howard Hughes Medical Institute, School of Medicine, University of California at San Diego, La Jolla, CA 92093-0668, USA.
Odorizzi
G
G
Estepa
E J
EJ
Emr
S D
SD
D016475:3T3 Cells / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002402:Cathepsin D / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D021381:Protein Transport; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D033921:Vesicular Transport Proteins; D000099177:Tsg101 Protein
D002352:Carrier Proteins; D002402:Cathepsin D; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D066246:ErbB Receptors; D005656:Fungal Proteins; D046911:Macromolecular Substances; D020794:Receptor Protein-Tyrosine Kinases; D017527:Receptor, IGF Type 2; D011990:Receptors, Transferrin; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D000099177:Tsg101 Protein; C425333:STP22 protein, S cerevisiae; C102954:VPS28 protein, S cerevisiae