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Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling

David Romano1, Lan K Nguyen1, David Matallanas1

  • 1Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.

Nature Cell Biology
|June 16, 2014
PubMed

Insights

Competing protein interactions regulate cellular signaling pathways, acting as switches. This mechanism integrates signals, controlling cell fate decisions like apoptosis and proliferation.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Systems biology

Background:

  • Signal transduction pathways must be coordinated for proper cellular function.
  • Raf-1 is a key regulator linking the MST-LATS and MEK-ERK pathways in mammalian cells.

Purpose of the Study:

  • To elucidate the regulatory mechanisms coordinating crosstalk between ERK and MST pathways.
  • To investigate how competing protein interactions drive signal transduction switches.

Main Methods:

  • Mathematical modeling of signaling pathways.
  • Experimental validation of predicted interactions.
  • Analysis of protein phosphorylation and binding affinities.

Main Results:

  • A complex network of competing protein interactions coordinates ERK and MST pathway crosstalk.
  • Phosphorylation-dependent binding affinity changes mediate steep signaling switches.
  • Akt phosphorylation of MST2 and LATS1 feedback phosphorylation of Raf-1 Ser259 were identified as key regulatory events.
  • Raf-1 Ser259 phosphorylation suppresses both MST2 and MEK signaling.

Conclusions:

  • Competing protein interactions provide a versatile mechanism for signal distribution.
  • This circuitry allows dynamic integration of graded signals into switch-like cellular responses.
  • Dysregulation of these interactions, as seen in Raf-1 Ser259 mutants or MST2 downregulation, can lead to aberrant cell proliferation, transformation, and survival.

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