Cytosolic lysine residues enhance anterograde transport and activation of the erythropoietin receptor

Liron Yosha, Orly Ravid, Nathalie Ben-Califa, Drorit Neumann

Research output: Contribution to journalArticlepeer-review


Lysine residues are key residues inmany cellular processes, in part due to their ability to accept a wide variety of post-translational modifications. In the present study, we identify the EPO-R [EPO (erythropoietin) receptor] cytosolic lysine residues as enhancers of receptor function. EPO-R drives survival, proliferation and differentiation of erythroid progenitor cells via binding of its ligand EPO.We mutated the five EPO-R cytosolic lysine residues to arginine residues (5KR EPO-R), eliminating putative lysinedependent modifications. Overexpressed 5KR EPO-R displayed impaired ubiquitination and improved stability compared with wt (wild-type) EPO-R. Unexpectedly, fusion proteins consisting of VSVGtsO45 (vesicular stomatitis virus glycoprotein temperaturesensitive folding mutant) with wt or 5KR EPO-R cytosolic domains demonstrated delayed glycan maturation kinetics upon substitution of the lysine residues. Moreover, VSVG-wt EPO-R, but not VSVG-5KR EPO-R, displayed endoplasmic reticulumassociated ubiquitination. Despite similar cell-surface EPObinding levels of both receptors and the lack of EPO-induced ubiquitination by 5KR EPO-R, the lysine-less mutant produced weaker receptor activation and signalling than the wt receptor. We thus propose that EPO-R cytosolic lysine residues enhance receptor function, most probably through ubiquitination and/or other post-translational modifications.

Original languageEnglish
Pages (from-to)509-518
Number of pages10
JournalBiochemical Journal
Issue number2
StatePublished - 15 Apr 2011


  • Endoplasmic reticulum
  • Post-translational modification
  • Signalling
  • Trafficking
  • Ubiquitin
  • Vesicular stomatitis virus glycoprotein


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