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

Roland Govers, Toine Ten Broeke, Peter Van Kerkhof, Alan L. Schwartz, Ger J. Strous

Research output: Contribution to journalArticlepeer-review

169 Scopus citations

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 DSWVE-FIELD 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.

Original languageEnglish
Pages (from-to)28-36
Number of pages9
JournalEMBO Journal
Volume18
Issue number1
DOIs
StatePublished - Jan 4 1999

Keywords

  • Endocytosis
  • Growth hormone receptor
  • Internalization
  • Ubiquitin

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