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J. Biol. Chem., Vol. 281, Issue 42, 31920-31929, October 20, 2006

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Csk-binding Protein Mediates Sequential Enzymatic Down-regulation and Degradation of Lyn in Erythropoietin-stimulated Cells^*

Evan Ingley¹, Jessica R. Schneider, Christine J. Payne, David J. McCarthy, Kenneth W. Harder^¶, Margaret L. Hibbs^¶, and S. Peter Klinken

From the Cell Signalling Group and the Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Perth, Western Australia 6000, Australia and the ^¶Ludwig Institute for Cancer Research, Melbourne Tumor Biology Branch, Royal Melbourne Hospital, Victoria 3050, Australia

We have shown previously that the Src family kinase Lyn is involved in differentiation signals emanating from activated erythropoietin (Epo) receptors. The importance of Lyn to red cell maturation has been highlighted by Lyn^-/- mice developing anemia. Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr³¹⁴, which recruited Csk/Ctk to suppress Lyn kinase activity. Intriguingly, phosphorylated Tyr³¹⁴ also bound suppressor of cytokine signaling 1 (SOCS1), another well characterized negative regulator of cell signaling, resulting in elevated ubiquitination, and degradation of Lyn. In Epo-responsive primary cells and cell lines, Lyn rapidly phosphorylated Cbp, suppressing Lyn kinase activity via Csk/Ctk within minutes of Epo stimulation; hours later, SOCS1 bound to Cbp and was involved in the ubiquitination and turnover of Lyn protein. Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.

Received for publication, March 21, 2006 , and in revised form, August 16, 2006.

^* This work was supported by Grants from the National Health and Medical Research Council (Grants 139008, 303101, and 403987), the Cancer Foundation of Western Australia, and the Medical Research Foundation of Royal Perth Hospital. 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.

¹ To whom correspondence should be addressed: Cell Signalling Group, Laboratory for Cancer Medicine Western Australian Institute for Medical Research Level 6, Medical Research Foundation Bldg. Rear 50 Murray St., Perth WA 6000 Australia. Tel.: 61-8-9224-0326; Fax: 61-8-9224-0322; E-mail: eingley{at}waimr.uwa.edu.au.

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