Galectin-3 regulates RasGRP4-mediated activation of N-Ras and H-Ras

Ruby Shalom-Feuerstein, Ran Levy, Victoria Makovski, Avraham Raz, Yoel Kloog*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Galectin-3 (Gal-3) is a pleiotropic β-galactoside-binding protein expressed at relatively high levels in human neoplasms. Its carbohydrate recognition domain (CRD) contains a hydrophobic pocket that can accommodate the farnesyl moiety of K-Ras. Binding of K-Ras to Gal-3 stabilizes K-Ras in its active (GTP-bound) state. Gal-3, which does not interact with N-Ras, was nevertheless shown to reduce N-Ras-GTP in BT-549 cells by an unknown mechanism that we explored here. First, comparative analysis of various cancer cell lines (glioblastomas, breast cancer cells and ovarian carcinomas) showed a positive correlation between low N-Ras-GTP/high K-Ras-GTP phenotype and Gal-3 expression levels. Next we found that epidermal growth factor-stimulated GTP loading of N-Ras, but not of K-Ras, is blocked in cells expressing high levels of Gal-3. Activation of Ras guanine nucleotide releasing proteins (RasGRPs) by phorbol 12-myristate 13-acetate (PMA) or downregulation of Gal-3 by Gal-3 shRNA increased the levels of N-Ras-GTP in Gal-3 expressing cells. We further show that the N-terminal domain of Gal-3 interacts with and inhibits RasGRP4-mediated GTP loading on N-Ras and H-Ras proteins. Growth of BT-549 cells stably expressing the Gal-3 N-terminal domain was strongly attenuated. Overall, these experiments demonstrate a new control mechanism of Ras activation in cancer cells whereby the Gal-3 N-terminal domain inhibits activation of N-Ras and H-Ras proteins.

Original languageEnglish
Pages (from-to)985-993
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Issue number6
StatePublished - Jun 2008


FundersFunder number
The Wolfson Family Foundation
National Institutes of Health
National Cancer InstituteR37CA046120
United States-Israel Binational Science Foundation


    • Cancer
    • Galectin-3
    • Ras
    • RasGRP4


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