EpoR Activation Stimulates Erythroid Precursor Proliferation by Inducing Phosphorylation of Tyrosine-88 of the CDK-Inhibitor p27Kip1

Fragka Pegka, Nathalie Ben-Califa, Drorit Neumann, Heidelinde Jäkel*, Ludger Hengst*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Erythrocyte biogenesis needs to be tightly regulated to secure oxygen transport and control plasma viscosity. The cytokine erythropoietin (Epo) governs erythropoiesis by promoting cell proliferation, differentiation, and survival of erythroid precursor cells. Erythroid differentiation is associated with an accumulation of the cyclin–dependent kinase inhibitor p27Kip1, but the regulation and role of p27 during erythroid proliferation remain largely unknown. We observed that p27 can bind to the erythropoietin receptor (EpoR). Activation of EpoR leads to immediate Jak2–dependent p27 phosphorylation of tyrosine residue 88 (Y88). This modification is known to impair its CDK–inhibitory activity and convert the inhibitor into an activator and assembly factor of CDK4,6. To investigate the physiological role of p27–Y88 phosphorylation in erythropoiesis, we analyzed p27Y88F/Y88F knock–in mice, where tyrosine–88 was mutated to phenylalanine. We observed lower red blood cell counts, lower hematocrit levels, and a reduced capacity for colony outgrowth of CFU–Es (colony–forming unit–erythroid), indicating impaired cell proliferation of early erythroid progenitors. Compensatory mechanisms of reduced p27 and increased Epo expression protect from stronger dysregulation of erythropoiesis. These observations suggest that p27–Y88 phosphorylation by EpoR pathway activation plays an important role in the stimulation of erythroid progenitor proliferation during the early stages of erythropoiesis.

Original languageEnglish
Article number1704
JournalCells
Volume12
Issue number13
DOIs
StatePublished - Jul 2023

Keywords

  • EpoR
  • cell cycle
  • erythropoiesis
  • p27
  • tyrosine phosphorylation

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