Reconstitution of mammary gland development in vitro: requirement of c-met and c-erbB2 signaling for branching and alveolar morphogenesis.
Reconstitution of mammary gland development in vitro: requirement of c-met and c-erbB2 signaling for branching and alveolar morphogenesis.
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体外乳腺发育的重构：C-MET和C-ERBB2信号传导对分支和肺泡形态发生的需求。
DOI：
10.1083/jcb.143.2.533
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发表时间：
1998-10-19
影响因子：
7.8
通讯作者：
Birchmeier, W
中科院分区：
文献类型：
--
作者：
Niemann, C;Brinkmann, V;Spitzer, E;Hartmann, G;Sachs, M;Naundorf, H;Birchmeier, W
我们已经建立了一个细胞培养系统，可以在发育中的乳腺中复制形态发生过程。基质培养的EpH4小鼠乳腺上皮细胞在c-met酪氨酸激酶受体配体肝细胞生长因子/分散因子（HGF/SF）存在下形成支管。相反，肺泡结构是在神经调节蛋白（c-erbB酪氨酸激酶受体的配体）存在的情况下形成的。这些不同的形态发生反应也可以在外植体培养的选定的人乳腺癌组织中观察到。HGF/ sf诱导的分支被PI3激酶抑制剂wortmannin和LY294002消除。相反，神经调节蛋白诱导的肺泡形态发生被MAPK激酶抑制剂PD98059所抑制。c-met介导的反应也可以通过转染c-met特异性底物Gab1来激发，Gab1可以激活PI3激酶途径。含有c-erbB2受体胞内结构域的激活杂交受体足以诱导肺泡形态发生，并且在c-erbB2底物结合结构域存在酪氨酸残基Y1028、Y1144、Y1201和Y1226/27。我们的数据表明，c-met和c-erbB2信号在乳腺上皮细胞中引发不同的形态发生程序：分支小管的形成依赖于一个涉及PI3激酶的途径，而肺泡的形态发生需要MAPK激酶。
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.