Review Nucleocytoplasmic lectins John L. Wang a, * , Richard M. Gray a , Kevin C. Haudek a , Ronald J. Patterson b a Department of Biochemistry and Molecular Biology, Michigan State University, 501 Biochemistry Building, East Lansing, MI 48824, USA b Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA Received 30 October 2003; received in revised form 10 March 2004; accepted 10 March 2004 Available online 10 May 2004 Abstract This review summarizes studies on lectins that have been documented to be in the cytoplasm and nucleus of cells. Of these intracellular lectins, the most extensively studied are members of the galectin family. Galectin-1 and galectin-3 have been identified as pre-mRNA splicing factors in the nucleus, in conjunction with their interacting ligand, Gemin4. Galectin-3, -7, and -12 regulate growth, cell cycle progression, and apoptosis. Bcl-2 and synexin have been identified as interacting ligands of galectin-3, involved in its anti-apoptotic activity in the cytoplasm. Although the annexins have been studied mostly as calcium-dependent phospholipid-binding proteins mediating membrane- membrane and membrane-cytoskeleton interactions, annexins A4, A5 and A6 also bind to carbohydrate structures. Like the galectins, certain members of the annexin family can be found both inside and outside cells. In particular, annexins A1, A2, A4, A5, and A11 can be found in the nucleus. This localization is consistent with the findings that annexin A1 possesses unwinding and annealing activities of a helicase and that annexin A2 is associated with a primer recognition complex that enhances the activity of DNA polymerase a. Despite these efforts and accomplishments, however, there is little evidence or information on an endogenous carbohydrate ligand for these lectins that show nuclear and/or cytoplasmic localization. Thus, the significance of the carbohydrate-binding activity of any particular intracellular lectin remains as a challenge for future investigations. D 2004 Elsevier B.V. All rights reserved. Keywords: Carbohydrate-binding protein; Galectin; Carbohydrate recognition 1. Introduction Lectins are non-immunoglobulin, nonenzymatic, carbo- hydrate-binding proteins. The natural, endogenous ligands for lectins are saccharide chains of glycoconjugates. Such glycoconjugates would most likely be found outside the cell or within lumenal spaces of cellular organelles. Consequent- ly, most of the studies on lectins have been performed in the context of secreted, cell surface-associated or intralumenal polypeptides. Thus, the words ‘nucleocytoplasmic lectins’ would have represented a conundrum to biologists some- time ago. Observations made over the past 20 years, however, have challenged the assumption that lectins and their ligands are exclusively extracellular. Both glycoconju- gates and carbohydrate-binding proteins have now been documented in the cytoplasm and the nucleus. Together with the other contributions in the present special issue on ‘‘Cytoplasmic Glycosylation,’’ our article on ‘‘Nucleocytoplasmic Lectins’’ aims to emphasize this key point. Because the most extensive studies on intra- cellular carbohydrate-binding proteins have been per- formed on certain members of the galectin family, we will highlight them as the paradigm for nucleocytoplas- mic lectins. In addition, we will discuss briefly other intracellular molecules described to exhibit lectin-like characteristics, including several members of the annexin family. Finally, we will describe intracellular activities that might suggest the requirement for recognition by a lectin. 2. Galectins 2.1. General statements on the galectin family The galectins are a family of carbohydrate-binding pro- teins that share two key properties: (a) binding affinity for h-galactosides; and (b) conserved sequence elements in the carbohydrate-binding site [1]. To date, 14 mammalian 0304-4165/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2004.03.013 * Corresponding author. Tel.: +1-517-353-9542; fax: +1-517-353-9334. E-mail address: wangj@msu.edu (J.L. Wang). www.bba-direct.com Biochimica et Biophysica Acta 1673 (2004) 75 – 93