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    • To date very little is

    2022-01-25

    To date, very little is known about the GEFs that regulate RhoA during amoeboid migration. GEF-H1, a RhoA GEF, is activated response to microtubule destabilization and promotes amoeboid migration (Eitaki, Yamamori, Meike, Yasui, & Inanami, 2012). Interestingly, the majority of SGI-1776 mg depleted of another RhoA GEF, NET1, switch to mesenchymal cell migration as their means of motility (Carr, Zuo, Oh, & Frost, 2013), indicating that tumor cells bear some degree of plasticity in their means of migration and have the ability to switch from one type of single cell migration to the other.
    Rho proteins regulate plasticity of single cell migration For metastatic dissemination of tumor cells, plasticity of cell migration is a prerequisite. This allows migrating cells to adapt to changes in the tumor microenvironment (Sahai, 2007). As mentioned above, the amoeboid and mesenchymal types of migration are interchangeable (Fig. 4). The suppression or activation of certain molecular pathways allows cells to transition from one type to the other, known as mesenchymal-amoeboid transition (MAT) or amoeboid-mesenchymal transition (AMT). The first observations of the involvement of Rho proteins in AMT were from Sahai and colleagues, who have shown that silencing of Rho/ROCK in amoeboid migrating melanoma cells induces a switch to mesenchymal migration (Sahai & Marshall, 2003). In follow-up studies, they have demonstrated that ROCK regulates the formation of actomyosin bundles in the cell cortex, just behind the invading edge (Wyckoff, Pinner, Gschmeissner, Condeelis, & Sahai, 2006). Later, 3-phosphoinositide-dependent protein kinase 1 (PDK1) was shown to activate ROCK1 at the plasma membrane by competing with the atypical GTPase and negative ROCK1 regulator, Rnd3. As such, silencing of PDK1 results in impaired amoeboid migration and a mesenchymal phenotype (Pinner & Sahai, 2008). Interestingly, just as in polarized migration, Rac and Rho negatively regulate each other and thereby regulate plasticity in migration. For example, active Rac promotes mesenchymal movement by activating WAVE2, thereby inhibiting the ROCK-dependent MLC2 phosphorylation required for amoeboid migration (Sanz-Moreno et al., 2008). Conversely, ROCK inactivates Rac by activating a Rac GAP, ArhGAP22 (Fig. 4). In addition, ROCK phosphorylates and thereby activates the Rac GAP FilGAP (Fig. 4) (Saito, Ozawa, Hibino, & Ohta, 2012). In breast carcinoma cells, depletion of FilGAP induces a mesenchymal phenotype; while conversely, overexpression of FilGAP induced an amoeboid phenotype. Since ROCK and Rac negatively regulate each other, inhibition of either pathway removes the block on the opposite pathway, thus promoting the opposite phenotype. Experimentally, such theory is further supported by studies on ROCK and Rac1 inhibition in different cancer cell models. However, while inhibition of ROCK in colorectal carcinoma cells induces AMT and inhibition of Rac1 in fibrosarcoma cells induces mesenchymal-amoeboid transition (MAT), inhibition of Rac1 in glioblastoma cells, which primarily exhibit mesenchymal migration, did not induce MAT but rather blocked overall migration (Yamazaki et al., 2009). This indicates that the effects of Rac1 and RhoA inhibition are dependent on the prefered type of migration exhibited by different cell types. Similar to Rac1, Cdc42 interacts with Rho/ROCK signaling and thereby regulates plasticity in cell migration. For example, cellular levels of RhoA are regulated by Smurf1. Cdc42 activates and recruits Smurf1 to the leading edge, thereby helping to maintain a mesenchymal phenotype via reduction of ROCK activity at the leading edge (Sahai, 2007). Inhibition of Cdc42 in mesenchymal cells induces Rho/ROCK-dependent MAT, while conversely, inhibition of Rho/ROCK resulted in AMT in amoeboid cells (Wilkinson et al., 2005). However, Cdc42 is also required for maintenance of amoeboid morphology and inhibition or knock-down of the DOCK10, a Cdcd42 GEF, or the Cdc42 effectors N-WASP or PAK2 promotes AMT (Gadea, Sanz-Moreno, Self, Godi, & Marshall, 2008). Nonetheless, when Cdc42 is inhibited, both mesenchymal and amoeboid cell movement are blocked, indicating that Cdc42 is important in both manners of single cell migration.