Tumor suppressor Hippo/MST1 kinase mediates chemotaxis by regulating spreading and adhesion

Yulia Artemenko, Petros Batsios, Jane Borleis, Zachary Gagnon, Josephine Lee, Meino Rohlfs, Doriane Sanséau, Stacey S. Willard, Michael Schleicher, Peter N. Devreotes

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)13632-13637
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number34
DOIs
StatePublished - Aug 21 2012

ASJC Scopus subject areas

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    Artemenko, Y., Batsios, P., Borleis, J., Gagnon, Z., Lee, J., Rohlfs, M., Sanséau, D., Willard, S. S., Schleicher, M., & Devreotes, P. N. (2012). Tumor suppressor Hippo/MST1 kinase mediates chemotaxis by regulating spreading and adhesion. Proceedings of the National Academy of Sciences of the United States of America, 109(34), 13632-13637. https://doi.org/10.1073/pnas.1211304109