title: Ubiquitination regulates the internalization, endolysosomal sorting, and signaling of the erythropoietin receptor.
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.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Gamze Betul
authors.initials: GB
authors.lastname: Bulut
authors.forename: Rita
authors.initials: R
authors.lastname: Sulahian
authors.forename: Yue
authors.initials: Y
authors.lastname: Ma
authors.forename: Nai-wen
authors.initials: NW
authors.lastname: Chi
authors.forename: Lily Jun-shen
authors.initials: LJ
authors.lastname: Huang
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000502:physiology; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D054875:Ubiquitination / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins