JAK1 PLAYS AN ESSENTIAL ROLE FOR RECEPTOR PHOSPHORYLATION AND STAT ACTIVATION IN RESPONSE TO GRANULOCYTE-COLONY-STIMULATING FACTOR

The proliferation and differentiation of neutrophils is regulated by g ranulocyte-specific colony-stimulating factor (G-CSF). G-CSF uses a re ceptor of the cytokine receptor superfamily and, in common with all me mbers of the family, induces the tyrosine phosphorylation and activati on of members of the Janus protein tyrosine kinase (Jak) family. In bo th myeloid cells and a human fibrosarcoma cell line expressing the G-C SF receptor, G-CSF induces the tyrosine phosphorylation and activation of Jak1, Jak2, end Tyk2. In addition, G-CSF induces the tyrosine phos phorylation 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 l ines lacking various Jaks, we show here that Jak1 is critical for G-CS F-mediated Stat activation, whereas Jak2 or Tyk2 are either not requir ed or play redundant or ancillary roles. In the absence of Jak1, G-CSF induces activation of Jak2 and Tyk2, but fails to induce receptor tyr osine phosphorylation and induces dramatically reduced levels of Stat activation. A kinase-inactive Jak2, when overexpressed in cells lackin g endogenous Jak2, can suppress Jak1 activation, receptor phosphorylat ion, and Stat activation, suggesting competition in the receptor compl ex either for Jak1 binding or substrates. Because the requirement for Jak1 is very similar to that previously shown for interleukin-6-signal ing, the data support the concept that the G-CSF receptor and gp130 ar e both structurally and functionally similar. (C) 1997 by The American Society of Hematology.