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Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain.

Publication ,  Journal Article
Arcasoy, MO; Karayal, AF
Published in: Biochim Biophys Acta
April 15, 2005

Erythropoietin receptor (EPOR) gene mutations leading to truncations of the cytoplasmic, carboxy-terminal region of EPOR have been described in some patients with primary familial and congenital polycythemia (PFCP), a disorder characterized by isolated erythrocytosis and increased sensitivity of erythroid progenitors to Epo. We studied the role of EPOR in the pathogenesis of PFCP and the requirement for intracytoplasmic tyrosine residues Y285 and Y344 in generation of Epo hypersensitivity phenotype. Interleukin-3-dependent hematopoietic cells were engineered to express variant human EPORs using retrovirus-mediated gene transfer. We introduced tyrosine to phenylalanine substitutions in EPOR-ME, a naturally occurring, mutant human EPOR (G5881T), truncated by 110 carboxy-terminal amino acids and associated with autosomal dominantly inherited PFCP. Cells expressing EPOR-ME exhibited increased Epo sensitivity compared to cells expressing wild type EPOR. Mutation of Y285 alone had a relatively minor effect on Epo hypersensitivity whereas mutation of Y344 resulted in loss of increased Epo sensitivity. Expression of a tyrosine-null truncated EPOR conferred further decrease of Epo-mediated proliferation suggesting that both Y285 and Y344 may contribute to proliferation signals. In the context of EPOR-ME, Y344 was required for Epo-induced Stat5 tyrosine phosphorylation. The positive effect of either Y285 or Y344 on cellular proliferation was associated with Epo-induced tyrosine phosphorylation of Stat1. These findings suggest that both tyrosine residues Y285 and Y344 in the cytoplasmic domain of EPOR-ME may contribute to increased Epo sensitivity that is characteristic of PFCP phenotype.

Duke Scholars

Published In

Biochim Biophys Acta

DOI

ISSN

0006-3002

Publication Date

April 15, 2005

Volume

1740

Issue

1

Start / End Page

17 / 28

Location

Netherlands

Related Subject Headings

  • Tyrosine
  • Trans-Activators
  • STAT5 Transcription Factor
  • STAT1 Transcription Factor
  • Receptors, Erythropoietin
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Protein Structure, Tertiary
  • Polycythemia
  • Phosphorylation
 

Citation

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ICMJE
MLA
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Arcasoy, M. O., & Karayal, A. F. (2005). Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain. Biochim Biophys Acta, 1740(1), 17–28. https://doi.org/10.1016/j.bbadis.2005.03.003
Arcasoy, Murat O., and Aysen F. Karayal. “Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain.Biochim Biophys Acta 1740, no. 1 (April 15, 2005): 17–28. https://doi.org/10.1016/j.bbadis.2005.03.003.
Arcasoy, Murat O., and Aysen F. Karayal. “Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain.Biochim Biophys Acta, vol. 1740, no. 1, Apr. 2005, pp. 17–28. Pubmed, doi:10.1016/j.bbadis.2005.03.003.

Published In

Biochim Biophys Acta

DOI

ISSN

0006-3002

Publication Date

April 15, 2005

Volume

1740

Issue

1

Start / End Page

17 / 28

Location

Netherlands

Related Subject Headings

  • Tyrosine
  • Trans-Activators
  • STAT5 Transcription Factor
  • STAT1 Transcription Factor
  • Receptors, Erythropoietin
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Protein Structure, Tertiary
  • Polycythemia
  • Phosphorylation