Arl4A interacts with Robo1 to promote cell migration via up‐regulating Cdc42 activation
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Abstract:
Cell migration is a highly regulated event that is initiated by protrusion of the cell membrane and actin reorganization. Robo1, a single‐pass transmembrane receptor, is crucial for neuronal guidance and cell migration via activating Cdc42 GTPase. ADP‐ribosylation factor (Arf)‐like 4A (Arl4A), one of Arf small GTPases, functions in cell morphology, cell migration, and actin cytoskeleton remodelling; however, the molecular mechanisms for Arl4A in cell migration is not clear. Here, we report that Arl4A binding to Robo1 modulates cell migration via promoting Cdc42 activation. We found that Arl4A interacts with Robo1 in a GTP‐dependent manner and residual 1394‐1399 of Robo1 is both required and sufficient for this interaction. Arl4A‐Robo1 interaction is essential for Arl4A‐induced cell migration and Cdc42 activation. We also showed that Arl4A binding to Robo1 decreases the association of a Cdc42‐GAP srGAP1 to Robo1. Furthermore, Slit2/Robo1 binding decreases Arl4A‐Robo1 interaction in vivo. Thus, our study reveals a novel mechanism that Arl4A participates in Slit2/Robo1 signaling on modulating cell motility via up‐regulating Cdc42 activation. Support or Funding Information NHRI‐EX106‐10601B1Keywords:
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Immense previous efforts have elucidated the core machinery in cell migration, actin remodeling regulated by Rho family small GTPases including RhoA, Cdc42, and Rac1; however, the spatiotemporal regulation of these molecules remains largely unknown. Here, we report that EGF induces biphasic Rac1 activation in the process of cell migration, and UTKO1, a cell migration inhibitor, inhibits the second EGF-induced wave of Rac1 activation but not the first wave. To address the regulation mechanism and role of the second wave of Rac1 activation, we identified 14-3-3ζ as a target protein of UTKO1 and also showed that UTKO1 abrogated the binding of 14-3-3ζ to Tiam1 that was responsible for the second wave of Rac1 activation, suggesting that the interaction of 14-3-3ζ with Tiam1 is involved in this event. To our knowledge, this is the first report to use a chemical genetic approach to demonstrate the mechanism of temporal activation of Rac1.
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Here we used RNA interference and examined possible redundancy amongst Rho GTPases in their mitotic role. Chromosome misalignment is induced significantly in HeLa cells by Cdc42 depletion and not by depletion of either one or all of the other four Cdc42‐like GTPases (TC10, TCL, Wrch1 or Wrch2), four Rac‐like GTPases or three Rho‐like GTPases. Notably, combined depletion of Cdc42 and all of the other four Cdc42‐like GTPases significantly enhances chromosomal misalignment. These observations suggest that Cdc42 is the primary GTPase functioning during mitosis but that the other four Cdc42‐like GTPases can also assume the mitotic role in its absence.
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Cdc42, a member of the Rho family of GTPases, has been shown to play a role in cell adhesion, cytoskeletal arrangement, phagocytosis and cell motility and migration, in addition to a host of other diverse biological processes. The function of Rho-family GTPases in disease pathogenesis has been well established and identification of small, cell permeable molecules that selectively and reversibly regulate Rho GTPases is of high scientific and potentially therapeutic interest. There has been limited success in identifying inhibitors that specifically interact with small Rho family GTPases. The identified probe, ML141 (CID-2950007), is demonstrated to be a potent, selective and reversible non-competitive inhibitor of Cdc42 GTPase suitable for in vitro assays, with low micromolar potency and selectivity against other members of the Rho family of GTPases (Rac1, Rab2, Rab7). Given the highly complementary nature of the function of the Rho family GTPases, Cdc42 selective inhibitors such as those reported here should help untangle the roles of the proteins in this family.
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Abstract Malignant glioblastomas are characterized by their ability to infiltrate into normal brain. We previously reported that binding of the multifunctional cytokine TNF-like weak inducer of apoptosis (TWEAK) to its receptor fibroblast growth factor–inducible 14 (Fn14) induces glioblastoma cell invasion via Rac1 activation. Here, we show that Cdc42 plays an essential role in Fn14-mediated activation of Rac1. TWEAK-treated glioma cells display an increased activation of Cdc42, and depletion of Cdc42 using siRNA abolishes TWEAK-induced Rac1 activation and abrogates glioma cell migration and invasion. In contrast, Rac1 depletion does not affect Cdc42 activation by Fn14, showing that Cdc42 mediates TWEAK-stimulated Rac1 activation. Furthermore, we identified two guanine nucleotide exchange factors (GEF), Ect2 and Trio, involved in TWEAK-induced activation of Cdc42 and Rac1, respectively. Depletion of Ect2 abrogates both TWEAK-induced Cdc42 and Rac1 activation, as well as subsequent TWEAK-Fn14–directed glioma cell migration and invasion. In contrast, Trio depletion inhibits TWEAK-induced Rac1 activation but not TWEAK-induced Cdc42 activation. Finally, inappropriate expression of Fn14 or Ect2 in mouse astrocytes in vivo using an RCAS vector system for glial-specific gene transfer in G-tva transgenic mice induces astrocyte migration within the brain, corroborating the in vitro importance of the TWEAK-Fn14 signaling cascade in glioblastoma invasion. Our results suggest that the TWEAK-Fn14 signaling axis stimulates glioma cell migration and invasion through two GEF-GTPase signaling units, Ect2-Cdc42 and Trio-Rac1. Components of the Fn14-Rho GEF-Rho GTPase signaling pathway present innovative drug targets for glioma therapy. Mol Cancer Res; 10(7); 958–68. ©2012 AACR.
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© 1997 Federation of European Biochemical Societies.
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