RT Journal Article
SR Electronic
T1 K-Ras Nanoclustering Is Subverted by Overexpression of the Scaffold Protein Galectin-3
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 6608
OP 6616
DO 10.1158/0008-5472.CAN-08-1117
VO 68
IS 16
A1 Shalom-Feuerstein, Ruby
A1 Plowman, Sarah J.
A1 Rotblat, Barak
A1 Ariotti, Nicholas
A1 Tian, Tianhai
A1 Hancock, John F.
A1 Kloog, Yoel
YR 2008
UL http://cancerres.aacrjournals.org/content/68/16/6608.abstract
AB 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] ©2008 American Association for Cancer Research.