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J. Biol. Chem. 269 (2): 1249-1256

© 1994 by The American Society for Biochemistry and Molecular Biology, Inc.

Protein kinase C-mediated serine phosphorylation directly activates Raf-1 in murine hematopoietic cells.

M P Carroll, and W S May

ABSTRACT Back to Top

Abstract: We have previously found that Raf-1, which is activated by hematopoietic growth factors in association with phosphorylation, is required for hematopoietic cell proliferation. Recently, 12-O-tetradecanoylphorbol 13-acetate has been found to mediate Raf-1 phosphorylation, suggesting that protein kinase C (PKC) may be involved in the Raf-1 activation mechanism(s). Since PKC can be activated by hematopoietic growth factors, it was investigated as a potential "Raf-1 kinase-kinase." Results demonstrate that bryostatin 1, a pharmacologic activator of PKC, induces activation of Raf-1 in FDC-P1 cells. PKC inhibitors H7 and staurosporine block both bryostatin 1- and interleukin-3-mediated Raf-1 phosphorylation and FDC-P1 cell proliferation. Additionally, an antisense c-raf oligodeoxyribonucleotide specifically inhibits bryostatin 1-mediated proliferation, indicating a necessary role for Raf-1 in PKC signaling. Purified PKC can phosphorylate Raf-1 serine residues to high stoichiometry in vitro. Comparative phosphopeptide maps localize two PKC phosphorylation sites to Raf-1 phosphopeptides isolated from hematopoietic growth factor- or bryostatin 1-stimulated cells. The sites of PKC-mediated Raf-1 phosphorylation are deduced to be Ser497 and Ser619. Furthermore, PKC-mediated serine phosphorylation is sufficient to activate the enzymatic function of Raf-1 in vitro. These findings demonstrate that activated PKC can promote hematopoietic cell growth by regulating the enzymatic activity of Raf-1 through direct serine phosphorylation.

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
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P. W. Howard and R. A. Maurer (1995)
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   Abstract »    Full Text »    PDF »
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B. E. Hawes, T. van Biesen, W. J. Koch, L. M. Luttrell, and R. J. Lefkowitz (1995)
J. Biol. Chem. 270, 17148-17153
   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
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M. A. Rizzo, K. Shome, S. C. Watkins, and G. Romero (2000)
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   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 275, 40856-40866
   Abstract »    Full Text »    PDF »
Kinase Suppressor of Ras Signals through Thr269 of c-Raf-1.
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   Abstract »    Full Text »    PDF »
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