Erythropoietin receptor signal transduction requires protein geranylgeranylation

Sumaya N. Hamadmad, Matthew K. Henry, Raymond J. Hohl

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Erythropoietin (Epo) acts through the erythropoietin receptor, 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 Janus kinase (Jak) 2, signal transducer and activator of transcription (Stat) 5, and extracellular signal-regulated kinase (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 3-hydroxy-3-methylglutaryl (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.

Original languageEnglish (US)
Pages (from-to)403-409
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume316
Issue number1
DOIs
StatePublished - Jan 1 2006

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Protein Prenylation
Erythropoietin Receptors
Erythropoietin
Signal Transduction
Prenylation
Lovastatin
Mevalonic Acid
Phosphorylation
STAT5 Transcription Factor
Janus Kinase 2
Hydroxymethylglutaryl CoA Reductases
Cytokine Receptors
Terpenes
Extracellular Signal-Regulated MAP Kinases
Post Translational Protein Processing
Apoptosis
Cell Line

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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abstract = "Erythropoietin (Epo) acts through the erythropoietin receptor, 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 Janus kinase (Jak) 2, signal transducer and activator of transcription (Stat) 5, and extracellular signal-regulated kinase (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 3-hydroxy-3-methylglutaryl (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.",
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Erythropoietin receptor signal transduction requires protein geranylgeranylation. / Hamadmad, Sumaya N.; Henry, Matthew K.; Hohl, Raymond J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 316, No. 1, 01.01.2006, p. 403-409.

Research output: Contribution to journalArticle

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