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  • Although historically the two ROCK


    Although historically, the two ROCK isoforms have been viewed as redundant, recent observations show that the two isoforms of ROCK might have different functions (Newell-Litwa et al., 2015). Knockdown of ROCK1 was found to result in cell rounding and a decrease in cell size while cells with knockdown of ROCK2 maintained a spread and elongated morphology (Jerrell, Leih, & Parekh, 2017).
    Rho proteins in mechanotransduction For metastasis to occur, a series of sequential steps is required that ultimately result in the migration of a malignant cell from its primary site towards a new site where it could adhere and form a secondary tumor. These sequential steps are collectively known as the metastatic cascade or the invasion-metastasis cascade (Poste and Fidler, 1980, Valastyan and Weinberg, 2011). Early during the metastatic cascade, tumor cells invade locally through the surrounding ECM and stromal cell layers, However, the tissue architecture of normal epithelium provides a barrier to invasiveness that first must be overcome by malignant cells before they can develop a migratory phenotype. In this section we highlight the role of the ECM in the tumor microenvironment in promoting tumor progression and discuss how Rho GTPases help integrate the signals coming from the ECM and change tumor cell behavior. Local invasion begins with tumor cells breaching the basement membrane. A compromised integrity of the basement membrane allows malignant cells to come in contact with stromal components, which results in aberrant cell polarity and invasion of stromal compartments by malignant cells (Cox & Erler, 2011). ECM components are degraded by a large variety of proteolytic enzymes of which MMPs are the best studied and therapeutically under investigation (Butcher et al., 2009, Vandenbroucke and Libert, 2014). Considering the importance of the ECM for cancer progression, correct understanding of the interplay between the ECM and cancer cells might hold the key to better cancer treatment and the molecular mechanisms that drive this are only recently beginning to emerge (Fang & Declerck, 2013). The physical microenvironment within a solid tumor differs from that of normal tissue in that there is increased mechanical compression due to tumor cell proliferation and increased deposition of stiff ECM (Paszek & Weaver, 2004). These changes in the tumor microenvironment alter the behavior of cancer cells through mechanotransduction pathways, which involve both the external environment and internal signaling (Huang & Ingber, 2005). Communication between the ECM and the cytoskeleton is mediated by conformational changes in proteins that respond to physical changes in the microenvironment, and translate these into chemical signals inside the cell (Ingber, 2006). Collectively, such proteins are known as mechanosensors of which integrins, are the most well studied in tumor progression (Guo & Giancotti, 2004). The perceived force promotes malignant transformation and motility through modulation of and p 00 dynamics by Rho GTPases (McBeath, Pirone, Nelson, Bhadriraju, & Chen, 2004). Moreover, mechanical stimuli such as high matrix stiffness can induce the translocation of the transcriptional co-activator myocardin-related transcription factor A (MRTF-A) in a RhoA/ROCK-dependent manner (Fig. 2) (Zhao et al., 2007). In the cytosol, MRTF-A sequesters with monomeric G-actin but activation of RhoA by increased matrix stiffness induces polymerization of G-actin to form F-actin filaments, thereby setting MRTF-A free to translocate to the nucleus where it acts as a transcriptional cofactor for serum response factor (SRF)-mediated gene transcription (Guettler et al., 2008, Miralles et al., 2003, Posern et al., 2004, Vartiainen et al., 2007). The importance of this pathway in tumor progression is demonstrated by the observation that depletion of MRTF-A or SRF attenuates cell motility and invasion of breast carcinoma and melanoma cells (Hermann et al., 2016, Medjkane et al., 2009). In a similar fashion, a stiff ECM can induce nuclear accumulation of Yes-associated protein (YAP) (Fig. 2) (Aragona et al., 2013, Dupont et al., 2011), which is often hyperactivated in tumors (Harvey et al., 2013, Johnson and Halder, 2014). Much like MRTF-A, YAP is a transcriptional co-activator of the transcriptional enhancer factor domain (TEAD)-containing transcription factors, although a number of other transcription factors have been reported to interact with YAP (Zhao et al., 2008, Zhao et al., 2008). YAP is a downstream mediator of the Hippo pathway and is functionally inhibited through phosphorylation by the large tumor suppressor kinases 1 and 2 (LATS1/2). Studies on YAP activation in cells exposed to a rigid ECM revealed that treatment with a RhoA inhibitor abolishes YAP nuclear accumulation while inhibition of LATS1/2 had no effect, indicating that RhoA and not LATS1/2 regulates YAP activation in mechanotransduction (Aragona et al., 2013, Dupont et al., 2011, Nardone et al., 2017). The discovery that RhoA is involved in activation of YAP was further extended upon by studies showing that YAP activation is regulated via GPCRs and downstream activation of RhoA (Mo et al., 2012, Yu et al., 2012). Importantly, expression of dominant negative RhoA was effective in blocked YAP activation, whereas constitutively active RhoA was sufficient to induce YAP nuclear translocation and tumor progression (Feng et al., 2014, Yu et al., 2012, Yu et al., 2014). A striking example of RhoA control over YAP nuclear translocation comes from the work on validating optogenetic tools to study RhoA in controlling cytoskeletal remodeling. Here, the authors show that by inducing RhoA membrane localization using a light sensitive subcellular localization switch, RhoA is cortically activated by RhoGEFs where it promotes cortical contractility (Valon et al., 2017). These changes in contractility are accompanied by a rapid and reversible nuclear YAP translocation. The reverse, in which RhoA can be inactivated by inducing mitochondrial localization using a light sensitive switch, is accompanied by a rapid and transient decrease in nuclear YAP localization. As such, optogenetic RhoA provides a new tool to locally study the mechanistic relationship between mechanical forces and YAP localization.