Abstract
The growth hormone receptor (GHR) is a member of the cytokine receptor family. Its function is to mediate cellular responses upon binding of growth hormone. Ligand binding induces dimerization and activation of the GHR. One mechanism by which the GHR is rapidly inactivated involves the ubiquitin conjugation system, a system implicated in the degradation of cytosolic and nuclear proteins. We have shown previously that the ubiquitin-conjugating system mediates internalization of the GHR. Here, we present evidence that in addition to the ubiquitin-dependent endocytosis signal, the cytosolic tail of the GHR contains a di-leucine motif. Upon truncation of the GHR at amino acid residue 349, this di-leucine motif is activated and mediates ubiquitin-independent internalization of the receptor. Di-leucine-mediated GHR internalization requires functional clathrin-coated pits and results in GHR transport to the lysosome. Although the full-length GHR internalizes independent of the di-leucine motif, this motif may function in internalization of GHR isoforms.
Highlights
Internalization of membrane proteins may be mediated via several amino acid sequences within the cytosolic domain [1, 2]
Ubiquitin-independent Internalization of a growth hormone receptor (GHR) Truncation Mutant—The GHR consists of 620 amino acid residues, of which 350 residues are located intracellularly (Fig. 1)
We showed that GHR truncation 1–349 internalized ligand and was ubiquitinated, while truncation mutants shorter than 314 amino acids residues were neither ubiquitinated nor able to internalize after binding of ligand
Summary
Internalization of membrane proteins may be mediated via several amino acid sequences within the cytosolic domain [1, 2]. Upon truncation of the GHR at amino acid residue 349, this di-leucine motif is activated and mediates ubiquitin-independent internalization of the receptor. The growth hormone receptor (GHR)1 is a mammalian plasma membrane protein whose internalization is mediated by the ubiquitin conjugation system [21].
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