Journal of Cell Science, Supplement 17,139-145 (1993) Printed in Great Britain © The Company of Biologists Limited 1993 139 Epithelial cell adhesion and development of cell surface polarity: possible mechanisms for modulation of cadherin function, organization and distribution Inke S. Nathke1, Lindsay E. Hinck12 and W. James Nelson1’2 Department of Molecular andCellular Physiology1 andThe Cancer BiologyProgram2, StanfordUniversitySchool of Medicine, Stanford, CA 94305-5426, USA SUMMARY Epithelial cell adhesion is principally regulated by cal- cium-dependent cell adhesion proteins, termed cad- herins. Recent studies indicate that cadherin function is modulated by a class of proteins, termed catenins, that bind to the cytoplasmic domain of cadherin. Here we INTRODUCTION Multicellular organisms are composed of heterogeneous cell types that are organized during development into dis tinct patterns to form tissues and organs. One of the impor tant, primary processes involved in regulating the estab lishment and maintenance of these patterns is cell-cell adhesion. Pioneering studies by Holtfreter and colleagues, and Steinberg and Moscona and colleagues established the central principle that the interaction between cells within a heterogeneous cell population is based upon the specificity and extent of adhesion between those cells; cells of the same type tended to aggregate and, therefore, be sorted out from the other cells (for discussion, see Trinkaus, 1984). The molecular basis for cell adhesion has since been shown to be due to the cell surface expression of a family of gly coproteins that bind with high specificity to each other on adjacent cells (Kemler, 1992a). These proteins are expressed in distinct patterns during tissue and organ mor phogenesis, suggesting that they play an important and direct role in the temporal and spatial regulation of cell interactions and cell sorting during tissue formation. Fur thermore, loss of expression of these proteins correlates with loss of intercellular adhesion, which is an early event in the induction of metastatic disease (Vieminckx et al., 1991). Two functionally distinct mechanisms of cell adhesion have been described: Ca2+-dependent, and Ca2+-indepen- dent adhesion (Takeichi, 1977). Both processes are medi ated by cell surface glycoproteins that have been classified into three major families of cell adhesion molecules (CAMs): the immunoglobulin (Ig) superfamily, integrins review the evidence that catenins regulate cadherin function in cell-cell adhesion, and discuss their role in inititiating cell surface polarity in epithelial cells. Key words: epithelia, adhesioii, cadherin, cytoskeleton, polarity and cadherins (Kemler, 1992b). N-CAM is a well charac terized member of the Ig superfamily of CAMs; its inter actions on adjacent cells are homotypic and Ca2+-indepen- dent (Goridis and Brunet, 1992). Early studies on the function of N-CAM in proteoliposomes provided direct bio chemical evidence of modulation of CAM avidity by CAM concentration; a 2-fold increase in the amount of N-CAM produced a 30-fold increase in its binding (Goridis and Brunet, 1992; Rutishauser et al., 1982). The integrin family of CAMs is primarily involved in cell interactions with the substratum (Sanchez-Madrid and Corbi, 1992). However, LFA-1, a member of the integrin family expressed on lym phocytes, interacts with I-CAM, a ligand on the surface of endothelial cells (Sanchez-Madrid and Corbi, 1992). The cadherin family of CAMs mediates Ca2+-dependent cell cell adhesion in a wide variety of cell types (Kemler, 1992a). Here we discuss possible mechanisms for modu lating cadherin function. CADHERIN FAMILY MEMBERS Three basic classes of cadherins have been characterized, E , P- and N-cadherin (Kemler, 1992a; Takeichi, 1977). Initial evidence that cadherins play a role in modulating cell inter actions was obtained using antibodies raised against the extracellular domain of a given cadherin, which was released from cells by trypsin in the presence of Ca2+ (Gumbiner and Simons, 1986). These antibodies inhibit cell-cell adhesion and cause clusters of cells to disaggregate in tissue culture. Addition of specific cadherin antibodies to preimplantation embryos blocks compaction, and their addition to develop