Identification of a novel ubiquitin conjugation motif, required for ligand‐induced internalization of the growth hormone receptor

Identification of a novel ubiquitin conjugation motif, required for ligand‐induced... In addition to its role in selective protein degradation, the conjugation of ubiquitin to proteins has also been implicated in the internalization of plasma membrane proteins, including the α‐factor receptor Ste2p, uracil permease Fur4p, epithelial sodium channel ENaC and the growth hormone receptor (GHR). Binding of GH to its receptor induces receptor dimerization, resulting in the activation of signal transduction pathways and an increase of GHR ubiquitination. Previously, we have shown that the ubiquitin conjugation system mediates GH‐induced GHR internalization. Here, we present evidence that a specific domain of the GHR regulates receptor endocytosis via the ubiquitin conjugation system. This ubiquitin‐dependent endocytosis (UbE) motif consists of the amino acid sequence DSWVEFIELD and is homologous to sequences in other proteins, several of which are known to be ubiquitinated. In addition, we show that GH internalization by a truncated GHR is independent of the presence of lysine residues in the cytosolic domain of this receptor, while internalization still depends on an intact ubiquitin conjugation system. Thus, GHR internalization requires the recruitment of the ubiquitin conjugation system to the GHR UbE motif rather than the conjugation of ubiquitin to the GHR itself. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

Identification of a novel ubiquitin conjugation motif, required for ligand‐induced internalization of the growth hormone receptor

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Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
DOI
10.1093/emboj/18.1.28
Publisher site
See Article on Publisher Site

Abstract

In addition to its role in selective protein degradation, the conjugation of ubiquitin to proteins has also been implicated in the internalization of plasma membrane proteins, including the α‐factor receptor Ste2p, uracil permease Fur4p, epithelial sodium channel ENaC and the growth hormone receptor (GHR). Binding of GH to its receptor induces receptor dimerization, resulting in the activation of signal transduction pathways and an increase of GHR ubiquitination. Previously, we have shown that the ubiquitin conjugation system mediates GH‐induced GHR internalization. Here, we present evidence that a specific domain of the GHR regulates receptor endocytosis via the ubiquitin conjugation system. This ubiquitin‐dependent endocytosis (UbE) motif consists of the amino acid sequence DSWVEFIELD and is homologous to sequences in other proteins, several of which are known to be ubiquitinated. In addition, we show that GH internalization by a truncated GHR is independent of the presence of lysine residues in the cytosolic domain of this receptor, while internalization still depends on an intact ubiquitin conjugation system. Thus, GHR internalization requires the recruitment of the ubiquitin conjugation system to the GHR UbE motif rather than the conjugation of ubiquitin to the GHR itself.

Journal

The EMBO JournalWiley

Published: Apr 4, 1999

Keywords: ; ; ;

References

  • Structure and functions of the 20S and 26S proteasomes
    Coux, O; Tanaka, K; Goldberg, AL
  • Linkage of the ubiquitin‐conjugating system and the endocytic pathway in ligand‐induced internalization of the growth hormone receptor
    Govers, R; van Kerkhof, P; Schwartz, AL; Strous, GJ
  • Roles of ubiquitin‐mediated proteolysis in cell cycle control
    Hershko, A
  • Role of the human transferrin receptor cytoplasmic domain in endocytosis: localization of a specific signal sequence for internalization
    Jing, SQ; Spencer, T; Miller, K; Hopkins, C; Trowbridge, IS
  • The linker region of this ABC‐transporter Ste6 mediates ubiquitination and fast turnover of the protein
    Kölling, R; Losko, S
  • Ligand‐induced polyubiquitination of receptor tyrosine kinases
    Mori, S; Claesson‐Welsh, L; Okuyama, Y; Saito, Y
  • Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination
    Staub, O; Gautschi, I; Ishikawa, T; Breitschopf, K; Ciechanover, A; Schild, L; Rotin, D
  • Association and colocalization of Eps15 with adaptor protein‐2 and clathrin
    Van Delft, S; Schumacher, C; Hage, W; Verkleij, AJ; Henegouwen, PMPVE

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