Ubiquitination Regulates the Internalization, Endolysosomal Sorting, and Signaling of the Erythropoietin Receptor

• Published in: The Journal of biological chemistry Vol. 286; no. 8; pp. 6449 - 6457
• Main Authors: Bulut, Gamze Betul, Sulahian, Rita, Ma, Yue, Chi, Nai-wen, Huang, Lily Jun-shen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.02.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cytokine; Down-Regulation - physiology; Endosomes - genetics; Endosomes - metabolism; Intracellular Trafficking; Mice; Mitogen-Activated Protein Kinase Kinases - genetics; Mitogen-Activated Protein Kinase Kinases - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Protein Transport - physiology; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; ras Proteins - genetics; ras Proteins - metabolism; Receptor Endocytosis; Receptors, Erythropoietin - genetics; Receptors, Erythropoietin - metabolism; Signal Transduction; Signal Transduction - physiology; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Ubiquitination; Ubiquitination - physiology; Intracellular Trafficking; Ubiquitination; Receptor Endocytosis; Signal Transduction; Cytokine
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.186890

Ubiquitination is a common mechanism of down-regulation of mitogenic receptors. Here, we show that ubiquitination of the erythropoietin receptor (EpoR) at Lys256 is necessary and sufficient for efficient Epo-induced receptor internalization, whereas ubiquitination at Lys428 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.