Received for publication July 13, 2005.
Revised September 29, 2005.
Accepted for publication September 30, 2005.

Erythropoietin Receptor Signal Transduction Requires Protein Geranylgeranylation

Abstract

Erythropoietin (Epo) acts through the erythropoietin receptor (EpoR), a member of the type-1 cytokine receptor family, to influence survival, proliferation, and differentiation of erythroid progenitors. Epo stimulation of factor-dependent 32D cells results in phosphorylation of many proteins including Jak2, Stat5, and Erk. Some of Epo-activated signaling proteins require isoprenylation, either farnesylation or geranylgeranylation, for post-translational modification. In this study we sought to characterize the interplay between protein isoprenylation and Epo signal transduction. Using two different Epo-responsive cell lines, we found that depletion of mevalonate and its isoprenoid derivatives using the HMG-CoA reductase inhibitor, lovastatin, impairs Epo signaling as assessed by phosphorylation of cellular substrates and inhibition of apoptosis. Interestingly, the effect of mevalonate depletion was prevented by adding back geranylgeranyl pyrophosphate but not farnesyl pyrophosphate. Furthermore, selective inhibition of protein geranylgeranylation mimicked the effect of lovastatin, whereas selective inhibition of farnesylation had no effect. These results indicate that protein geranylgeranylation, and not farnesylation, is important for proper Epo signal transduction.

Key words: Erythropoietin, Erythropoietin Receptor, GGPP, Geranylgeranylation, Isoprenylation, Signal Transduction

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