T. Kamei et al., Coendocytosis of cadherin and c-Met coupled to disruption of cell-cell adhesion in MDCK cells - regulation by Rho, Rac and Rab small G proteins, ONCOGENE, 18(48), 1999, pp. 6776-6784
Both E-cadherin, a cell-cell adhesion molecule, and c-Met, the hepatocyte g
rowth factor (HGF)/scatter factor (SF) receptor, were colocalized at cell-c
ell adhesion sites of MDCK cells. HGF/SF or a phorbol ester, 12-O-tetradeca
noylphorbol-13-acetate (TPA), induced disruption of cell-cell adhesion, whi
ch was accompanied by endocytosis of both E-cadherin and c-Met. Reduction o
f medium Ca2+ to a micromolar range showed the same effects. Re-increase in
medium Ca2+ to a millimolar range formed cell-cell adhesion, which was acc
ompanied by exocytosis of E-cadherin and c-Met, followed by their re-coloca
lization at the cell-cell adhesion sites. These results suggest that E-cadh
erin and c-Met are colocalized at cell-cell adhesion sites and undergo co-e
ndo-exocytosis. We have previously shown that TPA does not induce disruptio
n of cell-cell adhesion and subsequent scattering of MDCK cells stably expr
essing a dominant active mutant of RhoA or Rac1 small G protein or a domina
nt negative mutant of Rab5 small G protein. In these cell lines, the HGF- o
r TPA-induced coendocytosis of E-cadherin and c-Met was inhibited, but the
coendocytosis of E-cadherin and c-Met in response to reduction of medium Ca
2+ was not affected. Wortmannin, an inhibitor of phosphoinositide (PI) 3-ki
nase, inhibited the HGF-induced disruption of cell-cell junction and endocy
tosis of E-cadherin and c-Met, but not the TPA-induced ones. These results
suggest that disruption of cell-cell adhesion is involved in the HGF- or TP
A-induced coendocytosis of E-cadherin and c-Met in MDCK cells, and that the
Rho and Rab family members indirectly regulate this coendocytosis. In addi
tion, coendocytosis of E-cadherin and c-Met in response to HGF is partly me
diated by PI 3-kinase. The cross-talk between cell-cell and cell-matrix adh
erens junctions is discussed.