Distinct predictive performance of Rac1 and Cdc42 in cell migration

Masataka Yamao, Honda Naoki, Katsuyuki Kunida, Kazuhiro Aoki, Michiyuki Matsuda, Shin Ishii
<span title="">2015</span> <i title="Springer Nature"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/tnqhc2x2aneavcd3gx5h7mswhm" style="color: black;">Scientific Reports</a> </i> &nbsp;
We propose a new computation-based approach for elucidating how signaling molecules are decoded in cell migration. In this approach, we performed FRET time-lapse imaging of Rac1 and Cdc42, members of Rho GTPases which are responsible for cell motility, and quantitatively identified the response functions that describe the conversion from the molecular activities to the morphological changes. Based on the identified response functions, we clarified the profiles of how the morphology
more &raquo; ... lly changes in response to local and transient activation of Rac1 and Cdc42, and found that Rac1 and Cdc42 activation triggers laterally propagating membrane protrusion. The response functions were also endowed with property of differentiator, which is beneficial for maintaining sensitivity under adaptation to the mean level of input. Using the response function, we could predict the morphological change from molecular activity, and its predictive performance provides a new quantitative measure of how much the Rho GTPases participate in the cell migration. Interestingly, we discovered distinct predictive performance of Rac1 and Cdc42 depending on the migration modes, indicating that Rac1 and Cdc42 contribute to persistent and random migration, respectively. Thus, our proposed predictive approach enabled us to uncover the hidden information processing rules of Rho GTPases in the cell migration. Living cells process extracellular and intracellular information employing biochemical reaction network that we call "signal transduction". Great deal of molecular components in signal transduction has been extensively identified. However, the intracellular information processing remains poorly understood. Over the past decade, live-cell imaging techniques have been developed to visualize the dynamics of molecular activity in situ by means of biosensors, for example, based on the principle of Förster (or fluorescence) resonance energy transfer (FRET) 1-3 . Thus, we are entering a new era to investigate a question of how molecular signals are dynamically processed through signaling cascade. To examine this issue, we focused on cell migration as a model biological system, because both molecular activity (as input signal) and morphological changes (as output signal) during cell migration can be monitored by FRET imaging. Cell migration plays important roles in various biological functions, including wound healing, embryonic development, and cancer invasion 4 . This process is highly complex and coordinated in space and time; the protrusion and retraction of cellular membranes are primarily driven by the cytoskeleton, the reorganization of which is regulated by intracellular signaling 5,6 . Many studies have extensively investigated the molecular mechanisms involved in cell migration and have recognized the Rho small GTPases as key regulators of actin dynamics 7,8 . Rac1 and Cdc42 were classically thought to induce lamellipodia and filopodia, respectively 7,9 , and their downstream pathways have been well identified. For example, Rac1 activates WAVE complex and Arpin that respectively up-and down-regulates Arp2/3 complex to induce branched network of F-actin in lamellipodia 10 , whereas Cdc42 activates actin-associated proteins, including fascin, formin (mDia2) and Ena/VASP, to induce F-actin bundles in filopodia 11,12 . In addition, Rac1 and Cdc42 overlappingly activate the same collections of proteins to regulate F-actin,
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1038/srep17527">doi:10.1038/srep17527</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/26634649">pmid:26634649</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC4669460/">pmcid:PMC4669460</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/poosatasmnb2to4iuq6vdgxuue">fatcat:poosatasmnb2to4iuq6vdgxuue</a> </span>
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