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RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor

David Matallanas1, David Romano, Karen Yee

  • 1Signaling and Proteomics Laboratory, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.

Molecular Cell
|September 25, 2007
PubMed

Insights

The tumor suppressor RASSF1A triggers apoptosis by activating MST2 kinase signaling. Silencing of RASSF1A in cancers removes this crucial pro-apoptotic signal, promoting tumor growth.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • RASSF1A is a critical tumor suppressor gene frequently silenced in human cancers.
  • Alternative RASSF1 isoforms do not replace RASSF1A's function in cell-cycle arrest and apoptosis.
  • Apoptosis can be induced via Bax activation or MST kinase activation.

Purpose of the Study:

  • To elucidate the molecular mechanism of RASSF1A-induced apoptosis.
  • To identify the signaling pathway downstream of RASSF1A.

Main Methods:

  • Investigated the interaction between RASSF1A, Raf1, MST2, LATS1, YAP1, and p73.
  • Analyzed the role of RASSF1A in disrupting the Raf1-MST2 complex.
  • Examined the phosphorylation and nuclear translocation of YAP1.

Main Results:

  • RASSF1A disrupts the inhibitory Raf1-MST2 complex, enhancing MST2 interaction with LATS1.
  • RASSF1A-activated LATS1 phosphorylates YAP1, promoting its nuclear translocation.
  • Nuclear YAP1 associates with p73 to induce transcription of the proapoptotic gene puma.

Conclusions:

  • Identified a novel MST2-dependent effector pathway for RASSF1A's proapoptotic function.
  • Epigenetic silencing of RASSF1A in tumors abrogates a p73-mediated proapoptotic signal.

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