期刊
JOURNAL OF CELL SCIENCE
卷 127, 期 9, 页码 1938-1952出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.140657
关键词
Cancer; Cell invasion; c-Met; HIP1; Integrin; RhoA
类别
资金
- Academy of Finland
- ERC Starting Grant
- Sigrid Juselius Foundation
- Finnish Foundation for Cardiovascular Research and Finnish Cancer Organizations
- Drug Discovery Graduate School
- Finnish Cultural Foundation
- UK Medical Research Council
- Rosetrees Trust
- Medical Research Council [G0501003] Funding Source: researchfish
- MRC [G0501003] Funding Source: UKRI
Many carcinomas have acquired oncogenic mechanisms for activating c-Met, including c-Met overexpression and excessive autocrine or paracrine stimulation with hepatocyte growth factor (HGF). However, the biological outcome of c-Met activation through these distinct modes remains ambiguous. Here, we report that HGF-mediated c-Met stimulation triggers a mesenchymal-type collective cell invasion. By contrast, the overexpression of c-Met promotes cell rounding. Moreover, in a high-throughput siRNA screen that was performed using a library of siRNAs against putative regulators of integrin activity, we identified RhoA and the clathrin-adapter protein HIP1 as crucial c-Met effectors in these morphological changes. Transient RhoA activation was necessary for the HGF-induced invasion, whereas sustained RhoA activity regulated c-Met-induced cell rounding. In addition, c-Met-induced cell rounding correlated with the phosphorylation of filamin A and the downregulation of active cell-surface integrins. By contrast, a HIP1-mediated increase in beta 1-integrin turnover was required for the invasion triggered by HGF. Taken together, our results indicate that c-Met induces distinct cell morphology alterations depending on the stimulus that activates c-Met.
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