βTrCP controls GH receptor degradation via two different motifs.
The physiological roles of GH are broad and include metabolism regulation and promotion of somatic growth. Therefore, the responsiveness of cells to GH must be tightly regulated. This is mainly achieved by a complex and well-controlled mechanism of GH receptor (GHR) endocytosis. GHR endocytosis occurs independently of GH and requires the ubiquitin ligase, SCF (βTrCP) that is recruited to the ubiquitin-dependent endocytosis (UbE) motif in the cytoplasmic tail of the GHR. In this study we report that, in addition to the UbE motif, a downstream degron, DSGRTS, binds to βTrCP. The WD40 residues on βTrCP involved in the interaction with this sequence are identical to the ones necessary for binding the classical motif, DSGxxS, in inhibitor of NFκB signalling, and β-catenin. Previously, we showed that this motif is not involved in GH-induced endocytosis. We show here that the DSGRTS sequence significantly contributes to GHR endocytosis/degradation in basal conditions, whereas the UbE motif is involved both in basal and GH-induced conditions. These findings explain the high rate of GHR degradation under basal conditions, which is important for regulating the responsiveness of cells to GH.
Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Ana C
AC
da Silva Almeida
Ger J
GJ
Strous
Agnes G S H
AG
van Rossum
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004705:Endocytosis / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000737:chemistry / Q000378:metabolism*
C471644:BTRC protein, human; D008840:Microfilament Proteins; D011986:Receptors, Somatotropin; D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases