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J. Biol. Chem., Vol. 278, Issue 29, 26851-26861, July 18, 2003

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Erythropoietin Receptors Associate with a Ubiquitin Ligase, p33^RUL, and Require Its Activity for Erythropoietin-induced Proliferation^*

Ann D. Friedman , Dipali Nimbalkar  and Frederick W. Quelle   ¶

From the Department of Pharmacology and The Immunology Graduate Program, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242

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.

Received for publication, October 1, 2002 , and in revised form, May 9, 2003.

^* This work was supported by assistance from core facilities of the Holden Comprehensive Cancer Center at the University of Iowa, a grant from the Diabetes & Endocrinology Research Center at the University of Iowa (DK25295), and a Carver Trust Medical Research Initiative Grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Pharmacology, 2-210 Bowen Science Bldg., Carver College of Medicine, The University of Iowa, Iowa City, IA 52242. Tel.: 319-335-8539; Fax: 319-335-8930; E-mail: frederick-quelle{at}uiowa.edu.

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