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 Lys256 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. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.