Tyrosine 729 of the G-CSF receptor controls the duration of receptor signaling: involvement of SOCS3 and SOCS1.

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Zhuang D, Qiu Y, Haque SJ, Dong F

Tyrosine 729 of the G-CSF receptor controls the duration of receptor signaling: involvement of SOCS3 and SOCS1.

J Leukoc Biol. 2005 Oct;78(4):1008-15. Epub 2005 Jul 20.

PubMed ID

16033816 [ View in PubMed

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Abstract

Mutations in the granulocyte-colony stimulating factor receptor (G-CSF-R) gene resulting in carboxy terminal truncation have been associated with acute myeloid leukemia (AML). The truncated G-CSF-R from AML patients mediate enhanced and prolonged activation of signal transducer and activator of transcription 5 (Stat5). It has been shown that Src homology-2 (SH2)-containing tyrosine phosphatase-1 attenuates the intensity of G-CSF-induced Stat5 activation through interacting with the carboxy terminus of the G-CSF-R. Using a series of tyrosine-to-phenylalanine substitution mutants, we show here that tyrosine (Tyr) 729, located in the carboxy terminus of the G-CSF-R, controls the duration of G-CSF-stimulated activation of Stat5, Akt, and extracellular signal-regulated kinase 1/2. It is interesting that activation of these signaling molecules by G-CSF was prolonged by pretreating cells with actinomycin D or cyclohexamide, suggesting that de novo protein synthesis is required for appropriate termination of G-CSF-R signaling. The transcripts for suppressor of cytokine signaling 3 (SOCS3) and SOCS1 were up-regulated rapidly upon G-CSF stimulation. Expression of SOCS3 or SOCS1, but not SOCS2 and cytokine-inducible SH2 domain-containing protein, completely suppressed G-CSF-induced Stat5 activation but had only a weak effect on Stat5 activation mediated by the receptor mutant lacking Tyr 729. SOCS1 and SOCS3 also inhibited G-CSF-dependent cell proliferation, but the inhibitory effect of the two SOCS proteins on cell proliferation was diminished when Tyr 729 of the G-CSF-R was mutated. These data indicate that Tyr 729 of the G-CSF-R is required for SOCS1- and SOCS3-mediated negative regulation of G-CSF-R signaling and that the duration and intensity of G-CSF-induced Stat5 activation are regulated by two distinct mechanisms.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Filgrastim	Granulocyte colony-stimulating factor receptor	Protein	Humans	Yes	Stimulator	Details
Pegfilgrastim	Granulocyte colony-stimulating factor receptor	Protein	Humans	Yes	Agonist	Details