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

Ruby Shalom-Feuerstein, Sarah J. Plowman, Barak Rotblat, Nicholas Ariotti, Tianhai Tian, John F. Hancock, Yoel Kloog

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


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 signalregulated 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.

Original languageEnglish
Pages (from-to)6608-6616
Number of pages9
JournalCancer Research
Issue number16
StatePublished - 15 Aug 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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