Binding of Galectin-3, a β-Galactoside-binding Lectin, to MUC1 Protein Enhances Phosphorylation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2) and Akt, Promoting Tumor Cell Malignancy.
Both mucin 1 (MUC1) and galectin-3 are known to be overexpressed in various malignant tumors and associated with a poor prognosis. It has been extensively reported that MUC1 is involved in potentiation of growth factor-dependent signal transduction. Because some carbohydrate moieties carried on MUC1 change to preferable ones for binding of galectin-3 in cancer cells, we speculated that MUC1-mediated signaling may occur through direct binding of galectin-3. Immunochemical studies showed that the distribution of galectin-3 coincided with that of MUC1 in various human tumor tissues but not in human nonmalignant tissues, and the level of galectin-3 retained on the surface of various cancer cells paralleled that of MUC1. Treatment of MUC1-expressing cells with galectin-3 induced phosphorylation of ERK1/2 and Akt following enhanced phosphorylation of MUC1 C-terminal domain, consistently promoting tumor cell malignancy. It is also noted that this enhanced phosphorylation occurred independently of EGF receptor-mediated signaling in both EGF receptor- and MUC1-expressing cells, and multivalency of galectin-3 was important for initiation of MUC1-mediated signaling. Expectedly, both silencing of endogenous galectin-3 and treatment with galectin-3 antagonists down-regulated cell proliferation of MUC1-expressing cells. These results suggest that the binding of galectin-3 to MUC1 plays a key role in MUC1-mediated signaling. Thus, constitutive activation of MUC1-mediated signaling in an autocrine/paracrine manner caused by ligation of galectin-3 promotes uncontrolled tumor cell malignancy. This signaling may be another MUC1-mediated pathway and function in parallel with a growth factor-dependent MUC1-mediated signaling pathway.
From the Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan.
Yugo
Y
Mori
From the Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan.
Kaoru
K
Akita
the Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan, the Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan, and.
Masakazu
M
Yashiro
the Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
Tetsuji
T
Sawada
the Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
Kosei
K
Hirakawa
the Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan.
Takeomi
T
Murata
From the Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan, hnakada@cc.kyoto-su.ac.jp.
Hiroshi
H
Nakada
D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D037502:Galectin 3 / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D018396:Mucin-1 / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
D037502:Galectin 3; C060192:MUC1 protein, human; D018396:Mucin-1; D051057:Proto-Oncogene Proteins c-akt
cancer; cell motility; cell proliferation; galectin-3; mucin 1, cell surface-associated (MUC1); signal transduction