A Dominant Negative Erythropoietin (EPO) Receptor Inhibits EPO-dependent Growth and Blocks F-gp55-dependent Transformation

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 1994 Apr 1

PMID 8139531

Citations 12

Authors

D L Barber

J C DeMartino

M O Showers

A D DAndrea

Affiliations

Soon will be listed here.

Abstract

The erythropoietin receptor (EPO-R), a member of the cytokine receptor superfamily, can be activated to signal cell growth by binding either EPO or F-gp55, the Friend spleen focus-forming virus glycoprotein. Activation by F-gp55 results in constitutive EPO-R signalling and the first stage of Friend virus-induced erythroleukemia. We have generated a truncated form of the EPO-R polypeptide [EPO-R(T)] which lacks the critical cytoplasmic signal-transducing domain of the EPO-R required for EPO- or F-gp55-induced cell growth. EPO-R(T) specifically inhibited the EPO-dependent growth of EPO-R-expressing Ba/F3 cells without changing the interleukin-3-dependent growth of these cells. In addition, Ba/F3 cells that coexpressed wild-type EPO-R and EPO-R(T) were resistant to transformation by F-gp55 despite efficient expression of the F-gp55 transforming oncoprotein in infected cells. EPO-R(T) inhibited the EPO-dependent tyrosine phosphorylation of wild-type EPO-R, the tyrosine kinase (JAK2), and the SH2 adaptor protein (Shc). In conclusion, the EPO-R(T) polypeptide is a dominant negative polypeptide which specifically interferes with the early stages of EPO-R-mediated signal transduction and which prevents Friend virus transformation of erythroblasts.

Citing Articles

Random mutagenesis reveals residues of JAK2 critical in evading inhibition by a tyrosine kinase inhibitor.

Marit M, Chohan M, Matthew N, Huang K, Kuntz D, Rose D PLoS One. 2012; 7(8):e43437.

PMID: 22916261 PMC: 3420867. DOI: 10.1371/journal.pone.0043437.

The SH2B1 adaptor protein associates with a proximal region of the erythropoietin receptor.

Javadi M, Hofstatter E, Stickle N, Beattie B, Jaster R, Carter-Su C J Biol Chem. 2012; 287(31):26223-34.

PMID: 22669948 PMC: 3406707. DOI: 10.1074/jbc.M112.382721.

The erythropoietin receptor: molecular structure and hematopoietic signaling pathways.

Watowich S J Investig Med. 2011; 59(7):1067-72.

PMID: 21307776 PMC: 3134576. DOI: 10.2310/JIM.0b013e31820fb28c.

Oligomerization and scaffolding functions of the erythropoietin receptor cytoplasmic tail.

Watowich S, Liu K, Xie X, Lai S, Mikami A, Longmore G J Biol Chem. 1999; 274(9):5415-21.

PMID: 10026152 PMC: 2388248. DOI: 10.1074/jbc.274.9.5415.

Both the polycythemia- and anemia-inducing strains of Friend spleen focus-forming virus induce constitutive activation of the Raf-1/mitogen-activated protein kinase signal transduction pathway.

Muszynski K, Ohashi T, Hanson C, Ruscetti S J Virol. 1998; 72(2):919-25.

PMID: 9444983 PMC: 124561. DOI: 10.1128/JVI.72.2.919-925.1998.

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