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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Mst1 is an interacting protein that mediates PHLPPs' induced apoptosis

Meng Qiao1, Yaqi Wang, Xiaoen Xu

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.

Molecular Cell
|June 2, 2010
PubMed

Insights

PHLPP phosphatases induce cancer cell apoptosis independently of known targets. They activate Mst1, a protein kinase, which then triggers apoptosis, forming a regulatory triangle with Akt.

Area of Science:

  • Molecular biology
  • Cancer research
  • Cell signaling

Background:

  • PHLPP1 and PHLPP2 phosphatases are known tumor suppressors.
  • They inactivate Akt, a key signaling protein, in cancer cells.
  • The full role of PHLPPs, particularly in apoptosis, remains unclear.

Purpose of the Study:

  • To investigate the mechanism by which PHLPPs induce apoptosis in cancer cells.
  • To identify novel binding partners and substrates of PHLPPs involved in apoptosis.
  • To elucidate the role of PHLPPs in the Akt signaling pathway beyond direct Akt inhibition.

Main Methods:

  • Co-immunoprecipitation assays to identify binding partners.
  • In vitro and in vivo phosphatase assays to determine substrate interactions.
  • Western blotting to assess protein phosphorylation and activation states.
  • Analysis of downstream signaling pathways (p38, JNK) and apoptosis induction.

Main Results:

  • PHLPPs bind to and dephosphorylate Mst1 at the T387 site, activating Mst1.
  • Activated Mst1 phosphorylates and activates downstream kinases p38 and JNK.
  • This PHLPP-Mst1-p38/JNK axis induces apoptosis independently of known PHLPP targets like Akt.
  • Akt can phosphorylate Mst1 at T387, suggesting a feedback loop.

Conclusions:

  • PHLPPs induce cancer cell apoptosis through a novel pathway involving Mst1 activation.
  • A regulatory triangle between PHLPP, Akt, and Mst1 controls apoptosis and proliferation.
  • This pathway offers new therapeutic targets for cancer treatment.

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