Matrix-independent survival of human keratinocytes through an EGF receptor/MAPK-kinase-dependent pathway
Matrix-independent survival of human keratinocytes through an EGF receptor/MAPK-kinase-dependent pathway
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DOI：
10.1091/mbc.12.5.1519
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发表时间：
2001-05-01
影响因子：
3.3
通讯作者：
Rodeck, U
中科院分区：
文献类型：
--
作者：
Jost, M;Huggett, TM;Rodeck, U
正常上皮细胞在被拒绝与细胞外基质接触时经历凋亡，这一过程被称为“失巢凋亡”。“相反，恶性上皮细胞通常获得锚定独立性，即，在没有基质相互作用的情况下生存和生长的能力。在这里，我们提出了一个问题，即失巢凋亡是否受到EGF受体（EGFR）信号的影响。我们关注EGFR是因为EGFR信号在恶性上皮细胞中经常失调。我们证明，表皮生长因子受体的激活显着减轻了基质参与的要求，在悬浮培养的原代和永生化的人角质形成细胞的生存。通过EGFR激活对失巢凋亡的上皮细胞的保护与悬浮培养早期阶段持续的MAPK磷酸化相关，并且需要持续的MAPK磷酸化。有趣的是，高水平的MAPK磷酸化不仅需要EGFR介导的抗失巢凋亡的保护，而且还发生在悬浮培养的后期阶段作为caspase激活的结果。这些结果表明，EGFR激活有助于锚定非依赖性上皮细胞的生存，并确定MAPK激活作为一个重要的机制，在这个过程中。
Normal epithelial cells undergo apoptosis when they are denied contact with the extracellular matrix, in a process termed "anoikis." Conversely, malignant epithelial cells typically acquire anchorage independence, i.e., the capacity to survive and grow in the absence of matrix interaction. Here we asked the question whether anoikis is affected by signaling through the EGF receptor (EGFR). We focused on the EGFR because EGFR signaling is frequently deregulated in malignant epithelial cells. We demonstrate that EGFR activation markedly alleviated the requirement of matrix engagement for survival of primary and immortalized human keratinocytes in suspension culture. Protection of epithelial cells through EGFR activation against anoikis was associated with and required sustained MAPK phosphorylation during the early phase of suspension culture. Interestingly, high levels of MAPK phosphorylation were not only required for EGFR-mediated protection against anoikis but also occurred as a consequence of caspase activation at later stages of suspension culture. These results demonstrate that EGFR activation contributes to anchorage-independent epithelial cell survival and identify MAPK activation as an important mechanism in this process.