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J. Biol. Chem., Vol. 275, Issue 46, 36311-36315, November 17, 2000
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From the The
Phosphorylation of the
-Galactoside-binding Protein Galectin-3
Modulates Binding to Its Ligands*
,,§¶
Gastrointestinal Cancer Research Laboratory,
Henry Ford Health Sciences Center, Detroit, Michigan 48202, the
¶ Department of Medicine, the University of Michigan School of
Medicine, Ann Arbor, Michigan 48109, and the
§ Metastasis Research Program, Karmanos Cancer Institute and
the Department of Pathology, Wayne State University School of
Medicine, Detroit, Michigan 48201
-galactoside-binding protein galectin-3
has pleiotropic biological functions and has been implicated in cell
growth, differentiation, adhesion, RNA processing, apoptosis, and
malignant transformation. Galectin-3 may be phosphorylated at
N-terminal Ser6, but the role of phosphorylation in
determining interactions of this endogenous lectin with its ligands
remains to be elucidated. We therefore studied the effect of
phosphorylation on binding of galectin-3 to two of its reported
ligands, laminin and purified colon cancer mucin. Human recombinant
galectin-3 was phosphorylated in vitro by casein kinase I,
and separated from the native species by isoelectric focusing for use
in solid phase binding assays. Non-phosphorylated galectin-3 bound to
laminin and asialomucin in a dose-dependent manner with
half-maximal binding at 1.5 µg/ml. Phosphorylation reduced saturation
binding to each ligand by >85%. Ligand binding could be fully
restored by dephosphorylation with protein phosphatase type 1. Mutation
of galectin-3 at Ser6 (Ser to Glu) did not alter galectin
ligand binding. Metabolic labeling or separation by isoelectric
focusing confirmed the presence of phosphorylated galectin-3 species
in vivo in the cytosol of human colon cancer cells from
which ligand mucin was purified. Phosphorylation significantly reduces
the interaction of galectin-3 with its ligands. The process by which
phosphorylation modulates protein-carbohydrate interactions has
important implications for understanding the biological functions of
this protein, and may serve as an "on/off" switch for its sugar
binding capabilities.
*
This work was supported by the Research Service of the Henry
Ford Health Sciences Center and Research Foundation (to R. S. B.) and National Cancer Institute Grants R01CA 69480 (to R. S. B.) and R01CA 46120 (to A. R.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence and reprint requests should be
addressed: Henry Ford Health Sciences Center (K-7), 2799 W. Grand
Blvd., Detroit, MI 48202. Tel.: 313-916-9452; Fax: 313-916-9487;
E-mail: rbresal@mich.com.
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