Sequential Enzymatic Down-Regulation and Degradation of the Lyn Tyrosine Kinase in Erythropoietin-Stimulated Cells

Evan Ingley; Jessica R. Schneider; David J. McCarthy; Kenneth W. Harder; Margaret L. Hibbs; Warren S. Alexander; Douglas J. Hilton; Svend Peter Klinken

doi:10.1182/blood.V104.11.2166.2166

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Sequential Enzymatic Down-Regulation and Degradation of the Lyn Tyrosine Kinase in Erythropoietin-Stimulated Cells

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Sequential Enzymatic Down-Regulation and Degradation of the Lyn Tyrosine Kinase in Erythropoietin-Stimulated Cells

Evan Ingley, Jessica R. Schneider, David J. McCarthy, Kenneth W. Harder, Margaret L. Hibbs, Warren S. Alexander, Douglas J. Hilton and Svend Peter Klinken

Blood, Vol.104(11), pp.2166-2166

2004

DOI: https://doi.org/10.1182/blood.V104.11.2166.2166

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Abstract

Erythropoietin (Epo) is a key molecule in the development of red blood cells. We have shown previously that the tyrosine kinase Lyn is involved in differentiation signals emanating from an activated Epo-receptor. We have recently identified Cbp (Csk binding protein, a negative regulator of Src) as a novel interactor with Lyn. The proline-rich region of Cbp associates with the SH3 domain of Lyn, which then phosphorylates Cbp on multiple tyrosine residues forming additional binding sites for the Lyn SH2 domain. Phosphorylated Y314 of Cbp, in turn, recruits the negative regulators Csk/Ctk, which phosphorylate Lyn and down-regulate its kinase activity. A phosphotyrosine-specific yeast two-hybrid system we developed, confirmed that the SH2 domain of Csk associated with Y314 of Cbp. Significantly, another well characterized negative regulator, SOCS1, also bound this phosphorylated tyrosine residue, resulting in elevated ubiquitination and degradation of Lyn. Thus, Cbp co-ordinates a two step down-regulation of Lyn. In Epo-responsive J2E cells, Cbp is rapidly phosphorylated by Lyn and the enzymatic activity of Lyn is suppressed by Csk/Ctk after 10 minutes of Epo stimulation. Subsequently, SOCS1 is involved in the turn over of Lyn protein two hours post-Epo induction. These data demonstrate for the first time a two phase process regulated by Cbp for inactivating and degrading Lyn after Epo stimulation.

Details

Title: Sequential Enzymatic Down-Regulation and Degradation of the Lyn Tyrosine Kinase in Erythropoietin-Stimulated Cells
Authors/Creators: Evan Ingley - Harry Perkins Institute of Medical Research
Jessica R. Schneider - Harry Perkins Institute of Medical Research
David J. McCarthy - Harry Perkins Institute of Medical Research
Kenneth W. Harder - Ludwig Cancer Research
Margaret L. Hibbs - Ludwig Cancer Research
Warren S. Alexander - Walter and Eliza Hall Institute of Medical Research
Douglas J. Hilton - Walter and Eliza Hall Institute of Medical Research
Svend Peter Klinken - Harry Perkins Institute of Medical Research
Publication Details: Blood, Vol.104(11), pp.2166-2166
Publisher: American Society of Hematology
Identifiers: 991005614850007891
Murdoch Affiliation: School of Medical, Molecular and Forensic Sciences
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration
Citation topics: No Topic Assigned; No Topic Assigned; No Topic Assigned
Web Of Science research areas: Hematology
ESI research areas: Clinical Medicine