Distinct c-Met activation mechanisms induce cell rounding or invasion through pathways involving integrins, RhoA and HIP1

A Mai, Ghaffar Muharram, R Barrow-McGee, Habib Baghirov, Juha Rantala, S Kermorgant, Johanna Ivaska

Research output: Contribution to journalArticleScientificpeer-review

21 Citations (Scopus)

Abstract

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 b1-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
Original languageEnglish
Pages (from-to)1938-1952
JournalJournal of Cell Science
Volume127
Issue number9
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

Keywords

  • c-Met
  • cancer
  • cell invasion
  • HIP1
  • integrin
  • RhoA

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    Mai, A., Muharram, G., Barrow-McGee, R., Baghirov, H., Rantala, J., Kermorgant, S., & Ivaska, J. (2014). Distinct c-Met activation mechanisms induce cell rounding or invasion through pathways involving integrins, RhoA and HIP1. Journal of Cell Science, 127(9), 1938-1952. https://doi.org/10.1242/jcs.140657