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J. Cell Biol.,
Volume 143, Number 2, October 19, 1998 533-545
Max-Delbrück-Center for Molecular Medicine, D-13122 Berlin, Germany
We have established a cell culture system
that reproduces morphogenic processes in the developing mammary gland. EpH4 mouse mammary epithelial
cells cultured in matrigel form branched tubules in the
presence of hepatocyte growth factor/scatter factor
(HGF/SF), the ligand of the c-met tyrosine kinase receptor. In contrast, alveolar structures are formed in
the presence of neuregulin, a ligand of c-erbB tyrosine
kinase receptors. These distinct morphogenic responses
can also be observed with selected human mammary
carcinoma tissue in explant culture. HGF/SF-induced
branching was abrogated by the PI3 kinase inhibitors
wortmannin and LY294002. In contrast, neuregulin-
induced alveolar morphogenesis was inhibited by the MAPK kinase inhibitor PD98059. The c-met-mediated
response could also be evoked by transfection of a
c-met specific substrate, Gab1, which can activate the
PI3 kinase pathway. An activated hybrid receptor that
contained the intracellular domain of c-erbB2 receptor
suffices to induce alveolar morphogenesis, and was
observed in the presence of tyrosine residues Y1028,
Y1144, Y1201, and Y1226/27 in the substrate-binding
domain of c-erbB2. Our data demonstrate that c-met
and c-erbB2 signaling elicit distinct morphogenic programs in mammary epithelial cells: formation of
branched tubules relies on a pathway involving PI3 kinase, whereas alveolar morphogenesis requires MAPK
kinase.
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