Jp. Doyle et al., PROTEIN ZERO, A NERVOUS-SYSTEM ADHESION MOLECULE, TRIGGERS EPITHELIALREVERSION IN HOST CARCINOMA-CELLS, The Journal of cell biology, 131(2), 1995, pp. 465-482
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.