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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1626-1632
Regulation of Jak2 tyrosine kinase by protein kinase C during
macrophage differentiation of IL-3-dependent myeloid progenitor cells
Panu E. Kovanen,
Ilkka Junttila,
Kati Takaluoma,
Pipsa Saharinen,
Leena Valmu,
Weiqun Li, and
Olli Silvennoinen
From the Laboratory of Molecular Immunology, Institute of Medical
Technology, University of Tampere, Tampere, Finland; the Department of
Clinical Microbiology, Tampere University Hospital, Tampere, Finland;
the Department of Virology/Haartman Institute and the Department of
Biosciences, University of Helsinki, Helsinki, Finland; and the
Laboratory of Cellular and Molecular Biology, National Cancer
Institute, Bethesda, MD.
Differentiation of macrophages from myeloid progenitor cells depends
on a discrete balance between cell growth, survival, and
differentiation signals. Interleukin-3 (IL-3) supports the growth and
survival of myeloid progenitor cells through the activation of Jak2
tyrosine kinase, and macrophage differentiation has been shown to
be regulated by protein kinase C (PKC). During terminal differentiation of macrophages, the cells lose their mitogenic response
to IL-3 and undergo growth arrest, but the underlying signaling
mechanisms have remained elusive. Here we show that in
IL-3-dependent 32D myeloid progenitor cells, the
differentiation-inducing PKC isoforms PKC- and PKC-
specifically caused rapid inhibition of IL-3-induced tyrosine
phosphorylation. The target for this inhibition was Jak2, and the
activation of PKC by 12-O-tetradecanoyl-phorbol-13-acetate treatment
also abrogated IL-3-induced tyrosine phosphorylation of Jak2 in Ba/F3
cells. The mechanism of this regulation was investigated in 32D and
COS7 cells, and the inhibition of Jak2 required catalytic activity of
PKC- and involved the phosphorylation of Jak2 on serine and
threonine residues by the associated PKC-. Furthermore, PKC-
inhibited the in vitro catalytic activity of Jak2, indicating that Jak2 was a direct target for PKC-. In 32D cells, the
inhibition of Jak2 either by PKC-, tyrosine kinase inhibitor AG490,
or IL-3 deprivation caused a similar growth arrest. Reversal of
PKC--mediated inhibition by the overexpression of Jak2 promoted
apoptosis in differentiating 32D cells. These results demonstrate a
PKC-mediated negative regulatory mechanism of cytokine signaling and
Jak2, and they suggest that it serves to integrate growth-promoting and
differentiation signals during macrophage differentiation.
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