title: Regulation of Catalytic and Non-catalytic Functions of the Drosophila Ste20 Kinase Slik by Activation Segment Phosphorylation.
abstract: Protein kinases carry out important functions in cells both by phosphorylating substrates and by means of regulated non-catalytic activities. Such non-catalytic functions have been ascribed to many kinases, including some members of the Ste20 family. The Drosophila Ste20 kinase Slik phosphorylates and activates Moesin in developing epithelial tissues to promote epithelial tissue integrity. It also functions non-catalytically to promote epithelial cell proliferation and tissue growth. We carried out a structure-function analysis to determine how these two distinct activities of Slik are controlled. We find that the conserved C-terminal coiled-coil domain of Slik, which is necessary and sufficient for apical localization of the kinase in epithelial cells, is not required for Moesin phosphorylation but is critical for the growth-promoting function of Slik. Slik is auto- and trans-phosphorylated in vivo. Phosphorylation of at least two of three conserved sites in the activation segment is required for both efficient catalytic activity and non-catalytic signaling. Slik function is thus dependent upon proper localization of the kinase via the C-terminal coiled-coil domain and activation via activation segment phosphorylation, which enhances both phosphorylation of substrates like Moesin and engagement of effectors of its non-catalytic growth-promoting activity.
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada; Molecular Biology Program, Université de Montréal, Montreal, Quebec H3T 3J7, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Panneton
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada; Molecular Biology Program, Université de Montréal, Montreal, Quebec H3T 3J7, Canada.
authors.forename: Apurba
authors.initials: A
authors.lastname: Nath
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Fadi
authors.initials: F
authors.lastname: Sader
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Delaunay
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Ariane
authors.initials: A
authors.lastname: Pelletier
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada.
authors.forename: Dominic
authors.initials: D
authors.lastname: Maier
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Oh
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada; Molecular Biology Program, Université de Montréal, Montreal, Quebec H3T 3J7, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada; Department of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada. Electronic address: david.hipfner@ircm.qc.ca.
authors.forename: David R
authors.initials: DR
authors.lastname: Hipfner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D055162:Biocatalysis; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; C099886:moesin, Drosophila; D017346:Protein Serine-Threonine Kinases; C492662:Slik protein, Drosophila
keywords: Drosophila; Sterile20; activation segment; cell signaling; epithelium; non-catalytic activity; protein kinase; protein phosphorylation