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Vol. 19, Issue 11, 4776-4784, November 2008

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Activation of the MAPK Module from Different Spatial Locations Generates Distinct System Outputs

Kerry Inder^*, Angus Harding, Sarah J. Plowman^*,, Mark R. Philips, Robert G. Parton^*,||, and John F. Hancock^*,

*Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, Australia; Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia; New York University School of Medicine, New York, NY 10016; and ^||Centre for Microscopy and Microanalysis, University of Queensland, Brisbane 4072, Australia

Submitted April 21, 2008; Revised July 25, 2008; Accepted August 28, 2008
Monitoring Editor: J. Silvio Gutkind

The Ras/Raf/MEK/ERK (MAPK) pathway directs multiple cell fate decisions within a single cell. How different system outputs are generated is unknown. Here we explore whether activating the MAPK module from different membrane environments can rewire system output. We identify two classes of nanoscale environment within the plasma membrane. The first, which corresponds to nanoclusters occupied by GTP-loaded H-, N- or K-Ras, supports Raf activation and amplifies low Raf kinase input to generate a digital ERKpp output. The second class, which corresponds to nanoclusters occupied by GDP-loaded Ras, cannot activate Raf and therefore does not activate the MAPK module, illustrating how lateral segregation on plasma membrane influences signal output. The MAPK module is activated at the Golgi, but in striking contrast to the plasma membrane, ERKpp output is analog. Different modes of Raf activation precisely correlate with these different ERKpp system outputs. Intriguingly, the Golgi contains two distinct membrane environments that generate ERKpp, but only one is competent to drive PC12 cell differentiation. The MAPK module is not activated from the ER. Taken together these data clearly demonstrate that the different nanoscale environments available to Ras generate distinct circuit configurations for the MAPK module, bestowing cells with a simple mechanism to generate multiple system outputs from a single cascade.

Present address: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030.

Address correspondence to: John F. Hancock (John.F.Hancock{at}uth.tmc.edu)

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