title: The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338.
abstract: The pathway involving the signalling protein p21Ras propagates a range of extracellular signals from receptors on the cell membrane to the cytoplasm and nucleus. 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 changes. 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 factor. 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. 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 kinase, a mechanism could exist through which one Ras effector pathway can be influenced by another.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, The Walther Oncology Center, Indianapolis 46202, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: King
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.forename: B
authors.initials: B
authors.lastname: Diaz
authors.forename: D
authors.initials: D
authors.lastname: Barnard
authors.forename: W
authors.initials: W
authors.lastname: Miao
authors.forename: S
authors.initials: S
authors.lastname: Bagrodia
authors.forename: M S
authors.initials: MS
authors.lastname: Marshall
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D004789:Enzyme Activation; D004926:Escherichia coli; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000302:isolation & purification / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000201:enzymology; D054462:p21-Activated Kinases
chemical_list: D011994:Recombinant Proteins; D012694:Serine; C515911:PAK3 protein, human; C515913:Pak3 protein, rat; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D054462:p21-Activated Kinases