The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338

Alastair J. King, Huaiyu Sun, Bruce Diaz, Darlene Barnard, Wenyan Miao, Shubha Bagrodia and Mark S. Marshall ()
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Alastair J. King: Indiana University School of Medicine
Huaiyu Sun: The Walther Oncology Center
Bruce Diaz: Indiana University School of Medicine
Darlene Barnard: Indiana University School of Medicine
Wenyan Miao: Indiana University School of Medicine
Shubha Bagrodia: Section of Molecular & Cell Biology, Cornell University
Mark S. Marshall: Indiana University School of Medicine

Nature, 1998, vol. 396, issue 6707, 180-183

Abstract: Abstract The pathway involving the signalling protein p21Ras propagates a range of extracellular signals from receptors on the cell membrane to the cytoplasm and nucleus1. The Ras proteins regulate many effectors, including members of the Raf family of protein kinases. Ras-dependent activation of Raf-1 at the plasma membrane involves phosphorylation events, protein–protein interactions and structural changes2,3,4,5,6,7,8. Phosphorylation of serine residues 338 or 339 in the catalytic domain of Raf-1 regulates its activation in response to Ras, Src and epidermal growth factor9,10. Here we show that the p21-activated protein kinase Pak3 phosphorylates Raf-1 on serine 338 in vitro and in vivo. The p21-activated protein kinases are regulated by the Rho-family GTPases Rac and Cdc42 (ref. 11). Our results indicate that signal transduction through Raf-1 depends on both Ras and the activation of the Pak pathway. As guanine-nucleotide-exchange activity on Rac can be stimulated by a Ras-dependent phosphatidylinositol-3-OH kinase12,13, a mechanism could exist through which one Ras effector pathway can be influenced by another.

Date: 1998
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DOI: 10.1038/24184

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