The ubiquitin ligase SCF(betaTrCP) regulates the degradation of the growth hormone receptor.
SCF ubiquitin ligases play a pivotal role in the regulation of cell division and various signal transduction pathways, which in turn are involved in cell growth, survival, and transformation. SCF(TrCP) recognizes the double phosphorylated DSGPhiXS destruction motif in beta-catenin and IkappaB. We show that the same ligase drives endocytosis and degradation of the growth hormone receptor (GHR) in a ligand-independent fashion. The F-box protein beta-TrCP binds directly and specifically with its WD40 domain to a novel recognition motif, previously designated as the ubiquitin-dependent endocytosis motif. Receptor degradation requires an active neddylation system, implicating ubiquitin ligase activity. GHR-TrCP binding, but not GHR ubiquitination, is necessary for endocytosis. TrCP2 silencing is more effective on GHR degradation and endocytosis than TrCP1, although overexpression of either isoform restores TrCP function in silenced cells. Together, these findings provide direct evidence for a key role of the SCF(TrCP) in the endocytosis and degradation of an important factor in growth, immunity, and life span regulation.
van Kerkhof
Peter
P
Department of Cell Biology, University Medical Center Utrecht and Institute of Biomembranes, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Putters
Joyce
J
Strous
Ger J
GJ
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D002460:Cell Line; D004705:Endocytosis / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D011817:Rabbits; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
D020672:I-kappa B Proteins; D011986:Receptors, Somatotropin; D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins; D044843:SKP Cullin F-Box Protein Ligases