Essential role of ubiquitin-specific protease 8 for receptor tyrosine kinase stability and endocytic trafficking in vivo.
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.
Niendorf
Sandra
S
Leibniz Institut für Molekulare Pharmakologie, Krahmerstr. 6, D-12207 Berlin, Germany.
Oksche
Alexander
A
Kisser
Agnes
A
Löhler
Jürgen
J
Prinz
Marco
M
Schorle
Hubert
H
Feller
Stephan
S
Lewitzky
Marc
M
Horak
Ivan
I
Knobeloch
Klaus-Peter
KP
D000818:Animals; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D003643:Death; D004622:Embryo, Mammalian / Q000002:abnormalities; D004705:Endocytosis; D010450:Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D004795:Enzyme Stability; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D017353:Gene Deletion; D018390:Gene Targeting; D006801:Humans; D008099:Liver / Q000002:abnormalities; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D016296:Mutagenesis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase
D056827:Endosomal Sorting Complexes Required for Transport; D046912:Multiprotein Complexes; D025801:Ubiquitin; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D020893:Receptor, ErbB-3; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; C541536:Usp8 protein, mouse; C091939:ubiquitin isopeptidase