Abstract
Ubiquitination is a common mechanism of down-regulation of mitogenic receptors. Here, we show that ubiquitination of the erythropoietin receptor (EpoR) at Lys(256) is necessary and sufficient for efficient Epo-induced receptor internalization, whereas ubiquitination at Lys(428) promotes trafficking of activated receptors to the lysosomes for degradation. Interestingly, EpoR that cannot be ubiquitinated has reduced mitogenic activities and ability to stimulate the STAT5, Ras/MAPK, and PI3K/AKT signaling pathways. We therefore propose that ubiquitination of the EpoR critically controls both receptor down-regulation and downstream signaling.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Down-Regulation / physiology
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Endosomes / genetics
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Endosomes / metabolism*
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Mice
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Transport / physiology
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Erythropoietin / genetics
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Receptors, Erythropoietin / metabolism*
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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Signal Transduction / physiology*
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Ubiquitination / physiology*
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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Receptors, Erythropoietin
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STAT5 Transcription Factor
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase Kinases
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ras Proteins