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

19 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

Fingerprint

Integrins
Hepatocyte Growth Factor
Filamins
Clathrin
Small Interfering RNA
Libraries
Down-Regulation
Phosphorylation
Carcinoma
Proteins

Keywords

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

Cite this

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
Mai, A ; Muharram, Ghaffar ; Barrow-McGee, R ; Baghirov, Habib ; Rantala, Juha ; Kermorgant, S ; Ivaska, Johanna. / Distinct c-Met activation mechanisms induce cell rounding or invasion through pathways involving integrins, RhoA and HIP1. In: Journal of Cell Science. 2014 ; Vol. 127, No. 9. pp. 1938-1952.
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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",
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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, vol. 127, no. 9, pp. 1938-1952. https://doi.org/10.1242/jcs.140657

Distinct c-Met activation mechanisms induce cell rounding or invasion through pathways involving integrins, RhoA and HIP1. / Mai, A; Muharram, Ghaffar; Barrow-McGee, R; Baghirov, Habib; Rantala, Juha; Kermorgant, S; Ivaska, Johanna.

In: Journal of Cell Science, Vol. 127, No. 9, 2014, p. 1938-1952.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Mai, A

AU - Muharram, Ghaffar

AU - Barrow-McGee, R

AU - Baghirov, Habib

AU - Rantala, Juha

AU - Kermorgant, S

AU - Ivaska, Johanna

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AB - 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

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KW - cancer

KW - cell invasion

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KW - integrin

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