Ras proteins associate with cellular membranes by virtue of a series of post-translational modifications of their C-terminal CAAX sequences. The discovery that two of the three enzymes that modify CAAX proteins are restricted to the endoplasmic reticulum led to the recognition that all nascent Ras proteins transit endomembranes en route to the PM (plasma membrane) and that at steady-state N-Ras and H-Ras are highly expressed on the Golgi apparatus. To test the hypothesis that Ras proteins on internal membranes can signal, we developed a fluorescent probe that reports when and where in living cells Ras becomes active. We found that growth factors stimulated rapid and transient activation of Ras on the PM followed by delayed and sustained activation on the Golgi. We mapped one pathway responsible for this activity as involving PLCγ (phospholipase Cγ)/DAG (diacylglycerol)+Ca2+/RasGRP1. Using mammalian cells and fission yeast, we have shown that differential localization of activated Ras preferentially activates distinct signalling pathways. In very recent work, we have found that (i) the subcellular localization of K-Ras can be acutely modulated by phosphorylation of its C-terminal hypervariable region by PKC, (ii) among the membranes upon which phosphorylated K-Ras accumulates is the outer mitochondrial membrane and (iii) phosphorylated, internalized K-Ras promotes apoptosis. Thus the signalling output of Ras depends on its subcellular localization.
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Conference Article|
August 01 2005
Compartmentalized signalling of Ras
M.R. Philips
M.R. Philips
1
1Departments of Medicine, Cell Biology and Pharmacology, NYU School of Medicine, New York, NY, U.S.A.
1email philim01@med.nyu.edu
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Publisher: Portland Press Ltd
Received:
March 08 2005
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2005 The Biochemical Society
2005
Biochem Soc Trans (2005) 33 (4): 657–661.
Article history
Received:
March 08 2005
Citation
M.R. Philips; Compartmentalized signalling of Ras. Biochem Soc Trans 1 August 2005; 33 (4): 657–661. doi: https://doi.org/10.1042/BST0330657
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