Impaired Production and Increased Apoptosis of Neutrophils in Granulocyte Colony-Stimulating Factor Receptor–Deficient Mice

Liu, Fulu; Wu, Huai Yang; Wesselschmidt, Robin L.; Kornaga, Tad; Link, Daniel C.

doi:10.1016/s1074-7613(00)80504-x

Cited by 468 publications

(372 citation statements)

References 36 publications

(12 reference statements)

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“…In these experiments, a K D of ϳ210 nM was obtained. 4 The determined affinity is in the same range of the affinity measured in a recent study reporting a K D value of 42 nM for this interaction (32). This difference may be explained by the use of peptides corresponding to the amino acid sequence of human gp130 (pY759 motif (56), amino acid sequence: ␤A-TSSTVQpYSTVVHSG) vs murine gp130 (pY757 motif, Ref.…”

Section: Discussionsupporting

confidence: 59%

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

Hörtner

Nielsch

Mayr

et al. 2002

The Journal of Immunology

121

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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 (KD) for this interaction of around 2.8 μM. 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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Section: Discussionsupporting

confidence: 59%

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

Hörtner

Nielsch

Mayr

et al. 2002

The Journal of Immunology

121

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“…This was demonstrated for the G-CSFRnull mouse. Mice with a null mutation of the G-CSFR, like G-CSF-null mice, had ineffective granulopoiesis with chronic neutropenia, a decrease in mature myeloid elements in their bone marrow and diminished neutrophil release from bone marrow Liu et al, 1996;Semerad et al, 2002). Surprisingly, however, the bone marrow of G-CSFR-deficient mice has only a modest reduction in the committed myeloid progenitors.…”

Section: Knockouts Of Cytokine Receptorsmentioning

confidence: 99%

Cytokine receptors and hematopoietic differentiation

2007

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“…Homozygous deletion of G-CSFR or G-CSF causes severe neutropenia in mice, 21,22 and heterozygous mutations of G-CSFR have been linked to sporadic cases of severe congenital neutropenia. 23 As both Gfi1 transcriptional regulation and G-CSF/ G-CSFR signaling are critical to neutrophil maturation, we have investigated whether their activities might be linked.…”

Section: Introductionmentioning

confidence: 99%

The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

Sierra

Sakakibara

Gasperini

et al. 2010

Blood

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The transcription factor growth factor independence 1 (Gfi1) and the growth factor granulocyte colony-stimulating factor (G-CSF) are individually essential for neutrophil differentiation from myeloid progenitors. Here, we provide evidence that the functions of Gfi1 and G-CSF are linked in the regulation of granulopoiesis. We report that Gfi1 promotes the expression of Ras guanine nucleotide releasing protein 1 (RasGRP1), an exchange factor that activates Ras, and that RasGRP1 is required for G-CSF signaling through the Ras/ mitogen-activated protein/extracellular signal-regulated kinase (MEK/Erk) pathway. Gfi1-null mice have reduced levels of RasGRP1 mRNA and protein in thymus, spleen, and bone marrow, and Gfi1 transduction in myeloid cells promotes RasGRP1 expression. When stimulated with G-CSF, Gfi1-null myeloid cells are selectively defective at activating Erk1/2, but not signal transducer and activator of transcription 1 (STAT1) or STAT3, and fail to differentiate into neutrophils. Expression of RasGRP1 in Gfi1-deficient cells rescues Erk1/2 activation by G-CSF and allows neutrophil maturation by G-CSF. These results uncover a previously unknown function of Gfi1 as a regulator of RasGRP1 and link Gfi1 transcriptional control to G-CSF signaling and regulation of granulopoiesis

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Impaired Production and Increased Apoptosis of Neutrophils in Granulocyte Colony-Stimulating Factor Receptor–Deficient Mice

Cited by 468 publications

References 36 publications

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

Cytokine receptors and hematopoietic differentiation

The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

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