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J. Cell Biol.,
Volume 139, Number 3, November 3, 1997 785-795
* Division of Signal Transduction, Nara Institute of Science and Technology, Nara 630-01, Japan; The dynamic rearrangement of cell-cell
junctions such as tight junctions and adherens junctions
is a critical step in various cellular processes, including
establishment of epithelial cell polarity and developmental patterning. Tight junctions are mediated by
molecules such as occludin and its associated ZO-1 and
ZO-2, and adherens junctions are mediated by adhesion molecules such as cadherin and its associated
catenins. The transformation of epithelial cells by activated Ras results in the perturbation of cell-cell contacts. We previously identified the ALL-1 fusion partner from chromosome 6 (AF-6) as a Ras target. AF-6
has the PDZ domain, which is thought to localize AF-6
at the specialized sites of plasma membranes such as
cell-cell contact sites. We investigated roles of Ras and
AF-6 in the regulation of cell-cell contacts and found
that AF-6 accumulated at the cell-cell contact sites of
polarized MDCKII epithelial cells and had a distribution similar to that of ZO-1 but somewhat different
from those of catenins. Immunoelectron microscopy revealed a close association between AF-6 and ZO-1 at
the tight junctions of MDCKII cells. Native and recombinant AF-6 interacted with ZO-1 in vitro. ZO-1 interacted with the Ras-binding domain of AF-6, and this interaction was inhibited by activated Ras. AF-6
accumulated with ZO-1 at the cell-cell contact sites in
cells lacking tight junctions such as Rat1 fibroblasts and
PC12 rat pheochromocytoma cells. The overexpression of activated Ras in Rat1 cells resulted in the perturbation of cell-cell contacts, followed by a decrease of the
accumulation of AF-6 and ZO-1 at the cell surface.
These results indicate that AF-6 serves as one of the peripheral components of tight junctions in epithelial cells
and cell-cell adhesions in nonepithelial cells, and that
AF-6 may participate in the regulation of cell-cell contacts, including tight junctions, via direct interaction
with ZO-1 downstream of Ras.
Department of Molecular Cell
Biology, Weizmann Institute of Science, Rehovot 76100, Israel; § Department of Virology II, National Institute of Infectious
Diseases, Tokyo 162, Japan; and Department of Anatomy, Faculty of Medicine, Kyoto University, Kyoto 606, Japan
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