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Published online before print July 20, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0105032

Received for publication January 19, 2005.
Revised June 12, 2005.
Accepted for publication June 16, 2005.

Article

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

Dazhong Zhuang ^*, Yaling Qiu ^*, S. Jaharul Haque , and Fan Dong ^*@

*Department of Biological Sciences, University of Toledo, Ohio; and Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio

^@ To whom correspondence should be addressed. E-mail: fdong{at}utnet.utoledo.edu.

	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)-containng 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, 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.

Key Words: cytokines • signal transduction • granulopoiesis

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