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Structural basis for autoactivation of human Mst2 kinase and its regulation by RASSF5

Lisheng Ni1, Sheng Li, Jianzhong Yu

  • 1Department of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.

Structure (London, England : 1993)
|August 27, 2013
PubMed

Insights

The Hippo pathway

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The Hippo pathway is crucial for tissue homeostasis, regulating cell proliferation and apoptosis.
  • Upstream kinase activation in the Hippo pathway, particularly Mst1/2, is not fully understood.
  • Mst1/2 kinases and RASSF proteins share SARAH domains involved in dimerization.

Purpose of the Study:

  • To elucidate the structural mechanisms of Mst2 activation and regulation by RASSF5.
  • To investigate the role of SARAH domains in Mst2 homodimerization and autoactivation.
  • To determine how RASSF5 binding affects Mst2 kinase activity.

Main Methods:

  • X-ray crystallography was used to determine the structures of human Mst2 alone and complexed with RASSF5.
  • Biochemical assays were employed to assess Mst2 autoactivation and kinase activity.
  • Dimerization studies were performed to analyze the role of SARAH domains.

Main Results:

  • Mst2 activation occurs via transautophosphorylation dependent on SARAH-mediated homodimerization.
  • RASSF5 binding to Mst2 disrupts homodimers and inhibits autoactivation.
  • RASSF5 does not inhibit the kinase activity of already activated Mst2.

Conclusions:

  • RASSF5 exhibits dual regulatory roles on Mst2, acting as an inhibitor or potential activator based on binding timing.
  • Temporally sensitive RASSF functions allow the Hippo pathway to integrate various cellular signals.
  • Structural insights into Mst2-RASSF5 interactions provide a basis for understanding Hippo pathway regulation.

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