Erythropoietin receptors associate with a ubiquitin ligase, p33RUL, and require its activity for erythropoietin-induced proliferation

Ann D Friedman; Dipali Nimbalkar; Frederick W Quelle

doi:10.1074/jbc.M210039200

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Erythropoietin receptors associate with a ubiquitin ligase, p33RUL, and require its activity for erythropoietin-induced proliferation

Journal article

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Erythropoietin receptors associate with a ubiquitin ligase, p33RUL, and require its activity for erythropoietin-induced proliferation

Ann D Friedman, Dipali Nimbalkar and Frederick W Quelle

The Journal of biological chemistry, Vol.278(29), pp.26851-26861

07/18/2003

DOI: 10.1074/jbc.M210039200

PMID: 12746455

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Abstract

The proliferation and survival of hematopoietic cells is strictly regulated by cytokine growth factors that act through receptors of the Type I cytokine receptor family, including erythropoietin (Epo) and its receptor, EpoR. Mitogenic signaling by these receptors depends on activation of Jak tyrosine kinases. However, other required components of this pathway have not been fully identified. In a screen for proteins that interact with EpoR and Jak2, we identified a novel member of the U-box family of ubiquitin ligases. This receptor-associated ubiquitin ligase, RUL, co-precipitated with EpoR from mammalian cells and mediated ubiquitination of EpoR. Also, endogenously expressed RUL was rapidly and transiently phosphorylated on serine after cytokine treatment of factor-dependent hematopoietic cells. Expression of ubiquitin ligase-deficient mutants of RUL inhibited Epo-induced expression of c-myc and bcl-2, two immediate-early genes normally associated with Epo-induced cell growth. Consistent with that finding, expression of mutant RUL also inhibited Epo-dependent proliferation and survival of factor-dependent cells. Together, these observations suggest that RUL is a required component of mitogenic signaling by EpoR. We also show that RUL is phosphorylated in response to growth factors that act through non-cytokine receptors, suggesting that RUL may function as a common regulator of mitogenesis.

Erythropoietin - pharmacology

Recombinant Proteins - metabolism

Amino Acid Sequence

Cell Line

Phosphorylation

Humans

Ligases - genetics

Ubiquitin - metabolism

Ligases - metabolism

Molecular Sequence Data

Recombinant Proteins - genetics

Cell Division - drug effects

Sequence Homology, Amino Acid

Animals

Mutagenesis

Cloning, Molecular

In Vitro Techniques

Receptors, Erythropoietin - metabolism

COS Cells

Details

Title: Subtitle: Erythropoietin receptors associate with a ubiquitin ligase, p33RUL, and require its activity for erythropoietin-induced proliferation
Creators: Ann D Friedman - Department of Pharmacology and The Immunology Graduate Program, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
Dipali Nimbalkar
Frederick W Quelle
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.278(29), pp.26851-26861
DOI: 10.1074/jbc.M210039200
PMID: 12746455
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: DK25295 / NIDDK NIH HHS
Language: English
Date published: 07/18/2003
Academic Unit: Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040540502771

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