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Molecular and Cellular Biology, July 2007, p. 5029-5039, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.01566-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo ^,

Sandra Niendorf,¹ Alexander Oksche,² Agnes Kisser,¹ Jürgen Löhler,³ Marco Prinz,⁴ Hubert Schorle,⁵ Stephan Feller,⁶ Marc Lewitzky,⁶ Ivan Horak,¹ and Klaus-Peter Knobeloch^1*

Leibniz Institut für Molekulare Pharmakologie, Abteilung Molekulare Genetik, Krahmerstr. 6, D-12207 Berlin, Germany,¹ Institut für Pharmakologie, Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, D-14195 Berlin, Germany,² Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, D-20251 Hamburg, Germany,³ Institut für Neuropathologie, Georg-August-Universität Göttingen, D-37075 Göttingen, Germany,⁴ Institut für Pathologie, Universität Bonn, D-53127 Bonn, Germany,⁵ Weatherall Institute of Molecular Medicine, Cancer Research UK Signalling Group, University of Oxford, Oxford OX3 9DS, United Kingdom⁶

Received 22 August 2006/ Returned for modification 12 October 2006/ Accepted 3 April 2007

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.

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* Corresponding author. Mailing address: Leibniz Institut für Molekulare Pharmakologie, Krahmerstr. 6, D-12207 Berlin, Germany. Phone: 493084371915. Fax: 493084371922. E-mail: knobeloch{at}fmp-berlin.de

Published ahead of print on 23 April 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, July 2007, p. 5029-5039, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.01566-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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