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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor
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Tumor suppressor Hippo/MST1 kinase mediates chemotaxis by regulating spreading and adhesion

Yulia Artemenko1, Petros Batsios, Jane Borleis

  • 1Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Proceedings of the National Academy of Sciences of the United States of America
|August 1, 2012
PubMed

Insights

The Ste20 kinase KrsB negatively regulates cell adhesion, impacting cell migration and chemotaxis. Its phosphorylation by chemoattractants dynamically controls adhesion, essential for cell movement.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Chemotaxis involves complex pathways coordinating cytoskeletal events for directed cell movement along chemoattractant gradients.
  • The Hippo/MST kinase pathway regulates cell proliferation and organ size, with roles in cell morphology and adhesion emerging.

Purpose of the Study:

  • To identify novel regulators of cell migration and chemotaxis in Dictyostelium discoideum.
  • To elucidate the role of the Ste20 kinase KrsB, a Hippo/MST homolog, in regulating cell adhesion and movement.

Main Methods:

  • Forward genetic screen in Dictyostelium discoideum to identify mutants with altered chemotaxis.
  • Biochemical analysis of KrsB kinase activity, phosphorylation sites, and interactions with signaling pathways (G proteins, PI3K, TorC2).
  • Phenotypic analysis of krsB knockout cells, including cell spreading, substrate attachment, directional movement, and multicellular aggregation.

Main Results:

  • KrsB was identified as a negative regulator of cell spreading and substrate attachment.
  • Loss of KrsB function (krsB(-) cells) resulted in excessive adhesion, impaired directional movement, and prolonged aggregation.
  • Chemoattractants induced rapid, transient autophosphorylation of KrsB at T176 in a G protein-dependent, but PI3K/TorC2-independent manner.
  • Phosphorylated KrsB reduces substrate adhesion, suggesting its active form is crucial for decreasing cell-substrate interactions.

Conclusions:

  • KrsB functions as a critical regulator of cell adhesion, modulating cell migration and chemotaxis.
  • Dynamic cycling between active (phosphorylated) and inactive KrsB forms is essential for regulating cell adhesion during migration.
  • Hippo/MST proteins, including KrsB, play significant roles in cell morphological events beyond their known roles in cell growth regulation.

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