Involvement of the ubiquitin-proteasome pathway in the degradation of nontyrosine kinase-type cytokine receptors of IL-9, IL-2, and erythropoietin.
The ubiquitin-dependent proteasome-mediated (Ub-Pr) degradation pathway has been shown to regulate a large variety of substrates, including nuclear, cytosolic, and membrane proteins. In mammalian systems, polyubiquitin modification has been identified in a number of cell surface receptors for more than a decade; however, its biological significance has remained unclear until recently. For growth factor receptors with intrinsic tyrosine kinase domains, polyubiquitination is believed to trigger the internalization and subsequent degradation via the lysosomal pathway. In this study we provide the first evidence that non-tyrosine kinase-type cytokine surface receptors, IL-9R alpha-chain, IL-2 receptor ss-chain, and erythropoietin receptor, can be polyubiquitinated and degraded by proteasomes. The Ub-Pr pathway regulates both the basal level turnover and the ligand-induced degradation of the receptors. A previously identified putative molecular chaperon, valosin-containing protein, undergoes tyrosine phosphorylation in a cytokine-dependent manner and associates with the receptor complexes following receptor engagement, suggesting that valosin-containing protein may target the ubiquitinated receptors to the proteasome for degradation.
Yen
C H
CH
Intramural Research Support Program, Science Application International Corp. Frederick, MD, USA.
Yang
Y C
YC
Ruscetti
S K
SK
Kirken
R A
RA
Dai
R M
RM
Li
C C
CC
D000251:Adenosine Triphosphatases; D000818:Animals; D001704:Biopolymers / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology; D002999:Clone Cells; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004921:Erythropoietin / Q000378:metabolism* / Q000502:physiology; D007376:Interleukin-2 / Q000378:metabolism* / Q000502:physiology; D016906:Interleukin-9 / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000502:physiology; D009097:Multienzyme Complexes / Q000502:physiology*; D010766:Phosphorylation; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D053651:Receptors, Interleukin-9; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism / Q000502:physiology*; D000074405:Valosin Containing Protein
D001704:Biopolymers; D018797:Cell Cycle Proteins; D007376:Interleukin-2; D016906:Interleukin-9; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D018121:Receptors, Cytokine; D017467:Receptors, Erythropoietin; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D053651:Receptors, Interleukin-9; D014452:Ubiquitins; D004921:Erythropoietin; D025821:Polyubiquitin; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse