To regulate signal transmission from cell surface receptors to intracellular signaling cascades, K-Ras must be localized to the plasma membrane ( 5). Approximately 15% of human malignancies express mutant Ras proteins that are constitutively GTP loaded and unresponsive to extracellular stimuli, these oncogenic mutations are particularly prevalent in the K-ras gene and are associated with colon, lung, and pancreatic cancer ( 4). Therefore, in response to extracellular stimuli, Ras proteins can induce a range of cellular responses including proliferation, differentiation, and apoptosis by orchestrating the activation of specific intracellular signal transduction cascades ( 1– 3). Ras proteins are positioned at the junction between cell surface receptors and a number of intracellular signaling cascades, such as the Raf/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK MEK)/ERK, phosphatidylinositol-3-OH kinase/Akt, and RalGDS pathways. In the active GTP-bound state, Ras proteins recruit downstream effectors from the cytosol to the plasma membrane for activation. In response to growth factor receptor activation, Ras proteins are activated by guanine nucleotide exchange factors that stimulate GDP/GTP exchange. Ras proteins are guanine nucleotide binding proteins that act as molecular switches on the inner plasma membrane. One of the key regulators of intracellular signal transduction is the Ras family of proteins. Loss of cellular responsiveness to these cues leads to aberrant cell growth and tumor formation. To maintain tissue homeostasis, individual cells within the tissue must respond in concert to a given strength of signal input with a defined strength of signal output for a discrete period of time. Ĭell fate decisions are regulated by the magnitude and duration of a given stimulus. These results show that Gal-3 overexpression in breast cancer cells, which increases K-Ras signal output, represents oncogenic subversion of plasma membrane nanostructure. Thus, regulation of K-Ras nanocluster formation and signal output by Gal-3 critically depends on the integrity of the Gal-3 hydrophobic pocket. Gal-3(V125A) negatively regulates cell growth and reduces cellular transformation. 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. V125A substitution within this hydrophobic pocket yields a dominant negative Gal-3(V125A) mutant that inhibits K-Ras activity. The β-sheet layers of the Gal-3 carbohydrate recognition domain contain a hydrophobic pocket that may accommodate the farnesyl group of K-Ras. Importantly, we show that the cytosolic level of Gal-3 determines the magnitude of K-Ras.GTP nanoclustering and signal output. 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. The mechanism underlying K-Ras nanoclustering is unknown. The spatial organization of K-Ras proteins into nanoclusters on the plasma membrane is essential for high-fidelity signal transduction.
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