K-Ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3

Shalom-Feuerstein, R., Plowman, S.J., Rotblat, B., Ariott, N., Tian, T., Hancock, J.F. and Kloog, Y. (2008) K-Ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3. Cancer Research, 68, pp. 6608-6616. (doi: 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tian, Dr Tianhai
• Authors: Shalom-Feuerstein, R., Plowman, S.J., Rotblat, B., Ariott, N., Tian, T., Hancock, J.F., and Kloog, Y.
• Subjects: Q Science > QH Natural history > QH345 Biochemistry
• College/School: College of Science and Engineering > School of Mathematics and Statistics > Mathematics
• Journal Name: Cancer Research
• ISSN: 0008-5472
• ISSN (Online): 1538-7445