Dataset Information

Bistability in the Rac1, PAK and RhoA signalling network is a feature of cell motility.

ABSTRACT: Dynamic interactions between RhoA and Rac1, members of the Rho small GTPase family, play a vital role in the control of cell migration. Using predictive mathematical modelling and experimental validation in MDA-MB-231 mesenchymal breast cancer cells, we show that Rac1 and RhoA interactions via the PAK-family kinases can produce bistable, switch-like responses to a graded PAK inhibition. Using a small chemical inhibitor of PAK we confirm the model conjecture demonstrating that cellular RhoA and Rac activation levels respond in a bistable manner to PAK inhibition where for a given inhibition level these levels are high or low depending on the history of the system. Consequently, we show that downstream signalling, actin dynamics and cell migration also behave in a bistable fashion, displaying abrupt switches and hysteresis in response to PAK inhibition. In summary, our results demonstrate that PAK is a critical component in the Rac1-RhoA inhibitory crosstalk that mediates bistable GTPase activity and cell migration switches.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Alex von Kriegsheim

PROVIDER: MSV000080751 | MassIVE | Wed Mar 29 06:08:00 BST 2017

SECONDARY ACCESSION(S): PXD003213

REPOSITORIES: MassIVE

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Publications

Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches.

Byrne Kate M KM Monsefi Naser N Dawson John C JC Degasperi Andrea A Bukowski-Wills Jimi-Carlo JC Volinsky Natalia N Dobrzyński Maciej M Birtwistle Marc R MR Tsyganov Mikhail A MA Kiyatkin Anatoly A Kida Katarzyna K Finch Andrew J AJ Carragher Neil O NO Kolch Walter W Nguyen Lan K LK von Kriegsheim Alex A Kholodenko Boris N BN

Cell systems 20160127 1

Dynamic interactions between RhoA and Rac1, members of the Rho small GTPase family, play a vital role in the control of cell migration. Using predictive mathematical modeling, mass spectrometry-based quantitation of network components, and experimental validation in MDA-MB-231 mesenchymal breast cancer cells, we show that a network containing Rac1, RhoA, and PAK family kinases can produce bistable, switch-like responses to a graded PAK inhibition. Using a small chemical inhibitor of PAK, we demo ...[more]

PMID: 27136688

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Project description:Despite being subjected to high dose chemo and radiotherapy, glioblastoma (GBM) patients still encounter almost inevitable relapse due to the capability of tumor cells to disseminate and invade normal brain tissues. Moreover, the presence of a Cancer Stem Cell (CSC) subpopulation, already demonstrated to better resist and evade treatments, further frustrate potential therapeutic approaches. In this context, we previously demonstrated that GBM is characterized by a tightly regulated balance between the β-catenin cofactors TCF1 and TCF4, with high levels of TCF4 responsible for sustaining CSC in these tumors, thus supporting their aggressive features. Since Histone Deacetylase Inhibitors (HDI) have been reported to strongly reduce TCF4 levels in colon cancer cells, we hypothesized they could exert a similar therapeutic action also in GBM. Here, we treated primary GBM cultures with Trichostatin-A and Vorinostat, demonstrating their ability to strongly suppress the Wnt dependent pathways, thus promoting CSC differentiation, and concomitantly impairing GBM cell viability and proliferation. More interestingly, analysis of their molecular effects suggested a prominent HDI action against GBM cell motility/migration, that we demonstrated to be dependent on the inhibition of the RhoA-GTPase and interferon intracellular cascades. Our results suggest HDI as potential therapeutic agents in GBM through their action on multiple cancer hallmarks. Glioblastoma (GBM) is considered the deadliest brain tumor, with patients displaying a high incidence of relapse and a 3-year survival of only 3-5%. For these reasons, investigation of the molecular basis of the disease could provide novel targets for therapy and improve patient prognosis. Based on our previous data demonstrating that high levels of the transcription factor TCF4 (TCF7L2) sustain the aggressiveness and the stem cell features of these tumors, in this study we tested the ability of the histone deacetylase inhibitors (HDI) Trichostatin-A and Vorinostat to suppress TCF4 levels. We demonstrated that HDI treatment impairs proliferation and viability of GBM cells. Moreover, molecular analysis of HDI effects disclosed their ability to counteract tumor cell motility by affecting the RhoA-GTPase and the interferon pathways, supporting their further characterization as potential anti-GBM agents

Dataset Information

Bistability in the Rac1, PAK and RhoA signalling network is a feature of cell motility.

Publications

Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches.

Similar Datasets

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