PROTEIN ZERO, A NERVOUS-SYSTEM ADHESION MOLECULE, TRIGGERS EPITHELIALREVERSION IN HOST CARCINOMA-CELLS

Protein zero (P-o) is the immunoglobulin gene superfamily glycoprotein that mediates the self-adhesion of the Schwann cell plasma membrane t hat yields compact myelin. HeLa is a poorly differentiated carcinoma c ell line that has lost characteristic morphological features of the ce rvical epithelium from which it originated, Normally, HeLa cells are n ot self-adherent, However, when P-o is artificially expressed in this line, cells rapidly aggregate, and P-o concentrates specifically at ce ll-cell contact sites. Rows of desmosomes are generated at these inter faces, the plasma membrane localization of cingulin and ZO-1, proteins that have been shown to be associated with tight junctions, is substa ntially increased, and cytokeratins coalesce into a cohesive intracell ular network. Immunofluorescence patterns for the adherens junction pr oteins N-cadherin, alpha-catenin, and vinculin, and the desmosomal pol ypeptides desmoplakin, desmocollin, and desmoglein, are also markedly enhanced at the cell surface. Our data demonstrate that obligatory cel l-cell adhesion, which in this case is initially brought about by the hemophilic association of P-o molecules across the intercellular cleft , triggers pronounced augmentation of the normally sluggish or sub-bas al cell adhesion program in HeLa cells, culminating in suppression of the transformed state and reversion of the monolayer to an epithelioid phenotype, Furthermore, this response is apparently accompanied by an increase in mRNA and protein levels for desmoplakin and N-cadherin wh ich are normally associated with epithelial junctions, Our conclusions are supported by analyses of ten proteins we examined immunochemicall y (P-o, cingulin, ZO-1, desmoplakin, desmoglein, desmocollin, N-cadher in, alpha-catenin, vinculin, and cytokeratin-18), and by quantitative polymerase chain reactions to measure relative amounts of desmoplakin and N-cadherin mRNAs. P-o has no known signaling properties; the drama tic phenotypic changes we observed are highly likely to have developed in direct response to P-o-induced cell adhesion. More generally, the ability of this ''foreign'' membrane adhesion protein to stimulate des mosome and adherens junction formation by augmenting well-studied cadh erin-based adhesion mechanisms raises the possibility that perhaps any bona fide cell adhesion molecule, when functionally expressed, can en gage common intracellular pathways and trigger reversion of a carcinom a to an epithelial-like phenotype.