title: Jak1 plays an essential role for receptor phosphorylation and Stat activation in response to granulocyte colony-stimulating factor.
abstract: The proliferation and differentiation of neutrophils is regulated by granulocyte-specific colony-stimulating factor (G-CSF). G-CSF uses a receptor of the cytokine receptor superfamily and, in common with all members of the family, induces the tyrosine phosphorylation and activation of members of the Janus protein tyrosine kinase (Jak) family. In both myeloid cells and a human fibrosarcoma cell line expressing the G-CSF receptor, G-CSF induces the tyrosine phosphorylation and activation of Jak1, Jak2, and Tyk2. In addition, G-CSF induces the tyrosine phosphorylation of the receptor and members of the signal transducers and activators of transcription (Stat) family, including Stat3, as well as Stat1 and Stat5, depending on the cells involved. Using mutant cell lines lacking various Jaks, we show here that Jak1 is critical for G-CSF-mediated Stat activation, whereas Jak2 or Tyk2 are either not required or play redundant or ancillary roles. In the absence of Jak1, G-CSF induces activation of Jak2 and Tyk2, but fails to induce receptor tyrosine phosphorylation and induces dramatically reduced levels of Stat activation. A kinase-inactive Jak2, when overexpressed in cells lacking endogenous Jak2, can suppress Jak1 activation, receptor phosphorylation, and Stat activation, suggesting competition in the receptor complex either for Jak1 binding or substrates. Because the requirement for Jak1 is very similar to that previously shown for interleukin-6 signaling, the data support the concept that the G-CSF receptor and gp130 are both structurally and functionally similar.
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: K
authors.initials: K
authors.lastname: Shimoda
authors.forename: J
authors.initials: J
authors.lastname: Feng
authors.forename: H
authors.initials: H
authors.lastname: Murakami
authors.forename: S
authors.initials: S
authors.lastname: Nagata
authors.forename: D
authors.initials: D
authors.lastname: Watling
authors.forename: N C
authors.initials: NC
authors.lastname: Rogers
authors.forename: G R
authors.initials: GR
authors.lastname: Stark
authors.forename: I M
authors.initials: IM
authors.lastname: Kerr
authors.forename: J N
authors.initials: JN
authors.lastname: Ihle
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005354:Fibrosarcoma; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D051379:Mice; D008894:Milk Proteins; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D007377:Interleukin-3; D008894:Milk Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse