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Suppressor of cytokine signaling-3 is recruited to the activated granulocyte-colony stimulating factor receptor and modulates its signal transduction.
Hortner, Michael; Nielsch, Ulrich; Mayr, Lorenz M. et al.
2002In Journal of Immunology, 169 (3), p. 1219-27
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Keywords :
Carrier Proteins/physiology; Cells, Cultured; Granulocyte Colony-Stimulating Factor/pharmacology; Humans; Intracellular Signaling Peptides and Proteins; Monocytes/physiology; Neutrophils/physiology; Proteins/physiology; Receptors, Granulocyte Colony-Stimulating Factor/physiology; Repressor Proteins; Signal Transduction/physiology; Suppressor of Cytokine Signaling Proteins; Transcription Factors; Tyrosine/metabolism
Abstract :
[en] G-CSF is a polypeptide growth factor used in treatment following chemotherapy. G-CSF regulates granulopoiesis and acts on its target cells by inducing homodimerization of the G-CSFR, thereby activating intracellular signaling cascades. The G-CSFR encompasses four tyrosine motifs on its cytoplasmic tail that have been shown to recruit a number of regulatory proteins. Suppressor of cytokine signaling 3 (SOCS-3), also referred to as cytokine-inducible Src homolgy 2-containing protein 3, is a member of a recently discovered family of feedback inhibitors that have been shown to inhibit the Janus kinase/STAT pathway. In this study, we demonstrate that human SOCS-3 is rapidly induced by G-CSF in polymorphonuclear neutrophils as well as in the myeloid precursor cell line U937 and that SOCS-3 negatively regulates G-CSFR-mediated STAT activation. Most importantly, we show that SOCS-3 is recruited to the G-CSFR in a phosphorylation-dependent manner and we identify phosphotyrosine (pY)729 as the major recruitment site for SOCS-3. Furthermore, we demonstrate that SOCS-3 directly binds to this pY motif. Surface plasmon resonance analysis reveals a dissociation constant (K(D)) for this interaction of around 2.8 microM. These findings strongly suggest that the recruitment of SOCS-3 to pY729 is important for the modulation of G-CSFR-mediated signal transduction by SOCS-3.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Hortner, Michael
Nielsch, Ulrich
Mayr, Lorenz M.
Johnston, James A.
Heinrich, Peter C.
HAAN, Serge  ;  Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > Institute for Biochemistry
External co-authors :
yes
Language :
English
Title :
Suppressor of cytokine signaling-3 is recruited to the activated granulocyte-colony stimulating factor receptor and modulates its signal transduction.
Publication date :
2002
Journal title :
Journal of Immunology
ISSN :
0022-1767
Volume :
169
Issue :
3
Pages :
1219-27
Peer reviewed :
Peer reviewed
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since 25 April 2013

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