title: Tumor suppressor Hippo/MST1 kinase mediates chemotaxis by regulating spreading and adhesion.
abstract: Chemotaxis depends on a network of parallel pathways that coordinate cytoskeletal events to bias cell movement along a chemoattractant gradient. Using a forward genetic screen in Dictyostelium discoideum, we identified the Ste20 kinase KrsB, a homolog of tumor suppressors Hippo and MST1/2, as a negative regulator of cell spreading and substrate attachment. The excessive adhesion of krsB(-) cells reduced directional movement and prolonged the streaming phase of multicellular aggregation. These phenotypes depended on an intact kinase domain and phosphorylation of a conserved threonine (T176) within the activation loop. Chemoattractants triggered a rapid, transient autophosphorylation of T176 in a heterotrimeric G protein-dependent and PI3K- and TorC2-independent manner. The active phosphorylated form of KrsB acts to decrease adhesion to the substrate. Taken together these studies suggest that cycling between active and inactive forms of KrsB may provide the dynamic regulation of cell adhesion needed for proper cell migration and chemotaxis. KrsB interacts genetically with another D. discoideum Hippo/MST homolog, KrsA, but the two genes are not functionally redundant. These studies show that Hippo/MST proteins, like the tumor suppressor PTEN and oncogenes Ras and PI3K, play a key role in cell morphological events in addition to their role in regulating cell growth.
authors: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Yulia
authors: Y
authors: Artemenko
authors: Petros
authors: P
authors: Batsios
authors: Jane
authors: J
authors: Borleis
authors: Zachary
authors: Z
authors: Gagnon
authors: Josephine
authors: J
authors: Lee
authors: Meino
authors: M
authors: Rohlfs
authors: Doriane
authors: D
authors: Sanséau
authors: Stacey S
authors: SS
authors: Willard
authors: Michael
authors: M
authors: Schleicher
authors: Peter N
authors: PN
authors: Devreotes
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002633:Chemotaxis; D004023:Dictyostelium; D019281:Dimerization; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D049452:Green Fluorescent Proteins / Q000737:chemistry; D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D015800:Protozoan Proteins / Q000235:genetics*; D013912:Threonine / Q000737:chemistry; D000099317:Hippo Kinases
chemical_list: D049452:Green Fluorescent Proteins; D017228:Hepatocyte Growth Factor; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D015800:Protozoan Proteins; D013912:Threonine; C082332:macrophage stimulating protein; C109163:STK24 protein, human; D000099317:Hippo Kinases