Reference : Suppressor of cytokine signaling-3 is recruited to the activated granulocyte-colony s...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
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. [> >]
Johnston, James A. [> >]
Heinrich, Peter C. [> >]
Haan, Serge mailto [Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > Institute for Biochemistry]
Journal of immunology
Yes (verified by ORBilu)
United States
[en] 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
[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.

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