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Nucleophosmin and nucleolin regulate K-Ras plasma membrane interactions and MAPK signal transduction
Journal article   Peer reviewed

Nucleophosmin and nucleolin regulate K-Ras plasma membrane interactions and MAPK signal transduction

Kerry L Inder, Chiyan Lau, Dorothy Loo, Natasha Chaudhary, Andrew Goodall, Sally Martin, Alun Jones, Dharini van der Hoeven, Robert G Parton, Michelle M Hill, …
The Journal of biological chemistry, Vol.284(41), pp.28410-28419
10/09/2009
DOI: 10.1074/jbc.M109.001537
PMID: 19661056
url
https://doi.org/10.1074/jbc.M109.001537View
Published (Version of record) Open Access

Abstract

The spatial organization of Ras proteins into nanoclusters on the inner leaflet of the plasma membrane is essential for high fidelity signaling through the MAPK pathway. Here we identify two selective regulators of K-Ras nanoclustering from a proteomic screen for K-Ras interacting proteins. Nucleophosmin (NPM) and nucleolin are predominantly localized to the nucleolus but also have extranuclear functions. We show that a subset of NPM and nucleolin localizes to the inner leaflet of plasma membrane and forms specific complexes with K-Ras but not other Ras isoforms. Active GTP-loaded and inactive GDP-loaded K-Ras both interact with NPM, although NPM-K-Ras binding is increased by growth factor receptor activation. NPM and nucleolin both stabilize K-Ras levels on the plasma membrane, but NPM concurrently increases the clustered fraction of GTP-K-Ras. The increase in nanoclustered GTP-K-Ras in turn enhances signal gain in the MAPK pathway. In summary these results reveal novel extranucleolar functions for NPM and nucleolin as regulators of K-Ras nanocluster formation and activation of the MAPK pathway. The study also identifies a new class of K-Ras nanocluster regulator that operates independently of the structural scaffold galectin-3.
 Animals Cell Line Cell Membrane - metabolism Cell Membrane - ultrastructure Cricetinae Cricetulus Genes, ras Humans MAP Kinase Signaling System - physiology Mice Mitogen-Activated Protein Kinases - genetics Mitogen-Activated Protein Kinases - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Nucleolin Nucleophosmin Phosphoproteins - genetics Phosphoproteins - metabolism ras Proteins - genetics ras Proteins - metabolism Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism

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