K-Ras Nanoclustering Is Subverted by Overexpression of the Scaffold Protein Galectin-3
- 12 August 2008
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (16), 6608-6616
- https://doi.org/10.1158/0008-5472.can-08-1117
Abstract
The spatial organization of K-Ras proteins into nanoclusters on the plasma membrane is essential for high-fidelity signal transduction. The mechanism underlying K-Ras nanoclustering is unknown. We show here that K-Ras.GTP recruits Galectin-3 (Gal-3) from the cytosol to the plasma membrane where it becomes an integral nanocluster component. Importantly, we show that the cytosolic level of Gal-3 determines the magnitude of K-Ras.GTP nanoclustering and signal output. The β-sheet layers of the Gal-3 carbohydrate recognition domain contain a hydrophobic pocket that may accommodate the farnesyl group of K-Ras. V125A substitution within this hydrophobic pocket yields a dominant negative Gal-3(V125A) mutant that inhibits K-Ras activity. Gal-3(V125A) interaction with K-Ras.GTP reduces K-Ras.GTP nanocluster formation, which abrogates signal output from the Raf/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) pathway. Gal-3(V125A) negatively regulates cell growth and reduces cellular transformation. Thus, regulation of K-Ras nanocluster formation and signal output by Gal-3 critically depends on the integrity of the Gal-3 hydrophobic pocket. These results show that Gal-3 overexpression in breast cancer cells, which increases K-Ras signal output, represents oncogenic subversion of plasma membrane nanostructure. [Cancer Res 2008;68(16):6608–16]Keywords
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