Essential Role of Ubiquitin-specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking in Vivo.
From: Leibniz Institut für Molekulare Pharmakologie, Krahmerstr. 6, D-12207 Berlin, Germany.
Molecular and cellular biology
- Publish Date: Jul 2007
- ISSN: 0270-7306
- Volume: 27
- Issue: 13
- Pages: 5029-39
- Medium: Print
- Language: English
- Citation (JAMA): Niendorf Sandra, Oksche Alexander, Kisser Agnes, et al. Essential Role of Ubiquitin-specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking in Vivo.. Mol. Cell. Biol. Jul 2007;27:5029-39
Abstract
Posttranslational modification by ubiquitin controls multiple cellular functions and is counteracted by the activities of deubiquitinating enzymes. UBPy (USP8) is a growth-regulated ubiquitin isopeptidase that interacts with the HRS-STAM complex. Using Cre-loxP-mediated gene targeting in mice, we show that lack of UBPy results in embryonic lethality, whereas its conditional inactivation in adults causes fatal liver failure. The defect is accompanied by a strong reduction or absence of several growth factor receptor tyrosine kinases (RTKs), like epidermal growth factor receptor, hepatocyte growth factor receptor (c-met), and ERBB3. UBPy-deficient cells exhibit aberrantly enlarged early endosomes colocalizing with enhanced ubiquitination and have reduced levels of HRS and STAM2. Congruently immortalized cells gradually stop proliferation upon induced deletion of UBPy. These results unveil a central and nonredundant role of UBPy in growth regulation, endosomal sorting, and the control of RTKs in vivo.
Mesh Headings (Keywords): Animals, Cell Line, Transformed, Cell Proliferation, Death, Embryo, Mammalian, Endocytosis, Endopeptidases, Endosomes, Enzyme Stability, Fibroblasts, Gene Deletion, Gene Targeting, Humans, Liver, Mice, Multiprotein Complexes, Mutagenesis, Proto-Oncogene Proteins c-met, Receptor Protein-Tyrosine Kinases, Receptor, Epidermal Growth Factor, Receptor, erbB-3, Ubiquitin
Check for Full Text / PubMed Unique Identifier (PMID): 17452457
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