The Scribble complex localizes to the leading edge

The Scribble complex localizes to the leading edge in response to integrin engagement. There, Scribble controls the activation Rac and PAK via the Rac GEF β-Pix (Bahri et al., 2010), which is required for collective cell migration (Omelchenko et al., 2014). However, on the rear edge, Scribble can be recruited to adherens junctions by associating with E-cadherin, where it contributes to maintenance of cell-cell junctional stability by regulating β-Pix, Rac and PAK, which is crucial for collective cell migration (Nola et al., 2011, Qin et al., 2005, Tay et al., 2010, Yates et al., 2013). E-cadherin was considered to be the main cadherin involved in collective cell migration, but recently a key role for P-cadherin is emerging, driven by observations that P-cadherin depletion impairs collective cell migration in two and three dimensional in vitro experimental settings (Ng et al., 2012, Nguyen-Ngoc et al., 2012). However, the role of P-cadherin has remained elusive until the observation that P-cadherin expression predicts the amount of intercellular force, while E-cadherin expression predicts the build-up of intercellular force (Bazellieres et al., 2015). Importantly, a recent study identified that P-cadherin recruits β-Pix and thereby activates Cdc42, which underlies the cellular reorganizations observed in collective cell migration (Plutoni et al., 2016). Together, these findings draw a picture in which activation of Rho GTPases needs to be finely tuned to allow for adequate actomyosin contractility between multiple cells. A recent study applied a screening approach in to identify which exchange factors are involved in coordinating intercellular communication during collective cell migration and identified several RhoGEFs that are involved in this process, most notably ArhGEF3, ArhGEF18, PDZ-RhoGEF and p190-RhoGEF (Zaritsky et al., 2017). The findings in the abovementioned study suggest that, although necessary for generation of motility forces, actomyosin contractility acts as an inhibitor for cell-to-cell communication. This implies that during collective migration, contractility must be balanced between generation of motile forces and transmission of mechanical guidance cues between SGI-1776 mg (Zaritsky et al., 2017).
Rho proteins in amoeboid migration Most studies on the molecular mechanisms that underlie migration and tumor cell invasion have been carried out in in vitro two dimensional settings. However, tumor cells invade in a three dimensional extracellular space where cell movement is limited by surrounding ECM. Tumor cells can exploit the ECM degrading machinery to overcome this barrier. Therefore, many therapeutic strategies have explored the possibilities to inhibit ECM degrading proteases, however, to date only weak beneficial effects have been observed in animal models and clinical trials alike. In response to inhibition of ECM degrading proteases, carcinoma cells can exploit a different type of motility that does not rely on degradation of ECM. This type of migration is known as amoeboid migration and is characterized by flexible shape changes and a rounded cell morphology. Although earlier studies have proposed this type of migration to be a widespread phenomenon in cancer cell migration, the notion that protease-independent single cell migration is only plausible when the ECM is devoid of collagen cross-links, has put this under debate. Therefore, Weiss and colleagues noted that the design of studies on amoeboid migration insufficiently reproduce structural characteristics of collagen networks (Sabeh, Shimizu-Hirota, & Weiss, 2009). Amoeboid migrating cells use actomyosin contractility, stress fibers, and focal adhesions for propulsion, without the need for Rac/Cdc42-driven actin polymerization (Fig. 4). During amoeboid migration, RhoA/ROCK driven cortical actin contractility promotes the rapid remodeling of the cell cortex characteristic of this type of migration (Friedl and Wolf, 2003, Lammermann and Sixt, 2009, Wolf et al., 2003). Since an early observation on the role of ROCK in tumor cell motility (Itoh et al., 1999), many studies have reported that inhibition of ROCK activity leads to decreased tumor cell invasion and metastasis (de Toledo et al., 2012, Jeong et al., 2012, Liu et al., 2009, Zhu et al., 2011). The atypical Rnd family of Rho proteins are constitutively GTP-bound. Rnd1 and Rnd3 (also known as RhoE) contribute to loss of stress fibers and induce cell rounding, potentially by antagonizing Rho/ROCK-driven actomyosin contractility. Both Rnd1 and Rnd3 can interact with p190RhoGAP, thereby increasing the GAP activity of p190RhoGAP towards RhoA, resulting in decreased actomyosin contractility (Wennerberg et al., 2003). Such a process can be observed during formation and retraction of mebrane blebs during amoeboid migration. A recent study elegantly demonstrates that in the early stages of bleb formation, Rnd3 localizes to the inner mebrane of the blebs (Aoki et al., 2016). Here, the interaction with p190RhoGAP prevents the local activation of RhoA and actomyosin contractility. While the blebs grow in size, the concentration of Rnd3/p190RhoGAP complexes decreases, allowing to some degree of RhoA/ROCK activation. Subsequently, ROCK can phosphorylates Rnd3, thereby preventing the interaction with p190RhoGAP. This will eventually lead to RhoA/ROCK overcoming the Rnd3/p190RhoGAP brake on RhoA activation, and thereby promotes retraction of the bleb (Ikenouchi & Aoki, 2017).