Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells.
Galectin-3 (Gal-3), a pleiotropic carbohydrate-binding protein, is a selective binding partner of activated K-Ras-GTP. Because both proteins are antiapoptotic and associated with cancer progression, we questioned the possible functional role of Gal-3 in K-Ras activation. We found that overexpression of Gal-3 in human breast cancer cells (BT-549/Gal-3) coincided with a significant increase in wild-type (wt) K-Ras-GTP coupled with loss in wt N-Ras-GTP, whereas the nononcogenic Gal-3 mutant proteins [Gal-3(S6E) and Gal-3(G182A)] failed to induce the Ras isoform switch. Only wt Gal-3 protein coimmunoprecipitated and colocalized with oncogenic K-Ras, resulting in its activation with radical alterations in Ras signaling pathway, whereby the activation of AKT and Ral was suppressed and shifted to the activation of extracellular signal-regulated kinase (ERK). Specific inhibitors for Ras or mitogen-activated protein/ERK kinase (farnesylthiosalicylic acid and UO126, respectively) inhibited Gal-3-mediated apoptotic resistance and anchorage-independent growth functions. In conclusion, this study shows that Gal-3 confers on BT-549 human breast carcinoma cells several oncogenic functions by binding to and activation of wt K-Ras, suggesting that some of the molecular functions of Gal-3 are, at least in part, a result of K-Ras activation.
Shalom-Feuerstein
Ruby
R
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.
Cooks
Tomer
T
Raz
Avraham
A
Kloog
Yoel
Y
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D037502:Galectin 3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D009154:Mutation; D020033:Protein Isoforms; D018631:ras Proteins / Q000096:biosynthesis* / Q000235:genetics
D037502:Galectin 3; D020033:Protein Isoforms; D018631:ras Proteins