This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shalom-Feuerstein, R. Articles by Kloog, Y. Search for Related Content PubMed PubMed Citation Articles by Shalom-Feuerstein, R. Articles by Kloog, Y.

Galectin-3 Regulates a Molecular Switch from N-Ras to K-Ras Usage in Human Breast Carcinoma Cells

¹ Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel and ² Tumor Progression and Metastasis Program, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan

Requests for reprints: Yoel Kloog, Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, 69978 Tel-Aviv, Israel. Phone: 972-3-640-9699; Fax: 972-3-640-7643; E-mail: yoelk{at}tauex.tau.ac.il.

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.

This article has been cited by other articles:

				R. Shalom-Feuerstein, S. J. Plowman, B. Rotblat, N. Ariotti, T. Tian, J. F. Hancock, and Y. Kloog K-Ras Nanoclustering Is Subverted by Overexpression of the Scaffold Protein Galectin-3 Cancer Res., August 15, 2008; 68(16): 6608 - 6616. [Abstract] [Full Text] [PDF]

				Y. Fukaya, H. Shimada, L.-C. Wang, E. Zandi, and Y. A. DeClerck Identification of Galectin-3-binding Protein as a Factor Secreted by Tumor Cells That Stimulates Interleukin-6 Expression in the Bone Marrow Stroma J. Biol. Chem., July 4, 2008; 283(27): 18573 - 18581. [Abstract] [Full Text] [PDF]

				N. Mazurek, Y. J. Sun, K.-F. Liu, M. Z. Gilcrease, W. Schober, P. Nangia-Makker, A. Raz, and R. S. Bresalier Phosphorylated Galectin-3 Mediates Tumor Necrosis Factor-related Apoptosis-inducing Ligand Signaling by Regulating Phosphatase and Tensin Homologue Deleted on Chromosome 10 in Human Breast Carcinoma Cells J. Biol. Chem., July 20, 2007; 282(29): 21337 - 21348. [Abstract] [Full Text] [PDF]