Guanine nucleotide exchange factors for Rho GTPases: turning on the switch.

By A. Schmidt, A. Hall. Genes & Development, 2002

1,328 citations recorded by the source corpus.

Rho GTPases control many aspects of cell behavior through the regulation of multiple signal transduction pathways (Van Aelst and D’Souza-Schorey 1997; Hall 1998). Rho, Rac, and Cdc42 were first recognized in the early 1990s for their unique ability to induce specific filamentous actin structures in fibroblasts; stress fibers, lamellipodia/membrane ruffles, and filopodia, respectively (Hall 1998). Over the intervening years, evidence has accumulated to show that in all eukaryotic cells, Rho GTPases are involved in most, if not all, actin-dependent processes such as those involved in migration, adhesion, morphogenesis, axon guidance, and phagocytosis (Kaibuchi et al. 1999; Chimini and Chavrier 2000; Luo 2000). In addition to their well-established roles in controlling the actin cytoskeleton, Rho GTPases regulate the microtubule cytoskeleton, cell polarity, gene expression, cell cycle progression, and membrane transport pathways (Van Aelst and D’Souza-Schorey 1997; Daub et al. 2001; Etienne-Manneville and Hall 2001). With such a prominent role in so many aspects of cell biology, it is not surprising that they are themselves highly regulated. Like all GTPases, Rho proteins act as binary switches by cycling between an inactive (GDP-bound) and an active (GTP-bound) conformational state (Fig. 1; Van Aelst and D’Souza-Schorey 1997). The cell controls this switch by regulating the interconversion and accessibility of these two forms in a variety of ways. Guanine nucleotide exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate the activated form, which is then capable of recognizing downstream targets, or effector proteins. GTPase activating proteins (GAPs) accelerate the intrinsic GTPase activity of Rho family members to inactivate the switch. Finally, guanine nucleotide dissociation inhibitors (GDIs) interact with the prenylated, GDP-bound form to control cycling between membranes and cytosol. In theory, activation of a Rho GTPase could occur through stimulation of a GEF or inhibition of a GAP. In practice, however, all the evidence points to GEFs being the critical mediators of Rho GTPase activation, and this paper reviews our present understanding of how they do this. Structural features

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8cbf1ca5f6c82c62d1fe3a8d12074a622f69cc43

How researchers see this paper

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In Cell Biology

1. C. Der
2. Krister Wennerberg
3. K. Rossman
4. Alan Hall
5. A. Jaffe
6. M. Raftopoulou
7. J. Sondek
8. L. Van Aelst

In Molecular Biology

1. C. Der
2. K. Rossman
3. Krister Wennerberg
4. Tanja Kortemme
5. James S. Fraser
6. Amelie Stein
7. I. Dawid
8. Alan Hall

Citations in the corpus

• The Ras superfamily at a glance (2005, background): “Guanine-nucleotide-exchange factors (GEFs) promote formation of the active, GTP-bound form (Schmidt and Hall, 2002), whereas GTPase-activating proteins (GAPs) accelerate the intrinsic GTPase activity to promote formation of the inactive GDP-bound form (Bernards and Settleman, 2004).”
• GEFs and GAPs: critical elements in the control of small G proteins. (2007, background): “It was identified based on the observation that N-terminal truncated versions of these GEFs have transforming properties (Schmidt and Hall, 2002).”
• Rho-family GTPases: it's not only Rac and Rho (and I like it) (2004, background): “TC10 and TCL have yet to be to found to be regulated by GEFs of the Dbl family (Schmidt and Hall, 2002), which are thought to be the most common activators of Rho-family proteins.”
• Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation. (2003, background): “One possibility is that Cdc42N17 cross-inhibits Rac by titrating the Rac–GEF in the embryo, as some GEFs can bind and activate both Cdc42 and Rac (for review, see Schmidt and Hall 2002).”
• Control of protein signaling using a computationally designed GTPase/GEF orthogonal pair (2012, background): “F56 of Cdc42 has previously been implicated as a residue that defines the specificity of Cdc42 for various GEFs including ITSN (20, 31, 32).”
• The role of the Rho GTPases in neuronal development. (2005, background): “Guanine nucleotide exchange factors (GEFs) activate GTPases by enhancing the exchange of bound GDP for GTP (Schmidt and Hall 2002); GTPase activating proteins (GAPs) act as negative regulators of GTPases by enhancing the intrinsic rate of GTP hydrolysis of a GTPase (Bernards 2003; Bernards and…”
• GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors (2005, background): “So Dbl and Cdc24 represented the initial members of a new family of GEF”
• Cell migration: Rho GTPases lead the way. (2004, background): “…proteins (GAPs) negatively regulate the switch by enhancing its intrinsic GTPase activity and guanine nucleotide dissociation inhibitors (GDIs) are thought to block the GTPase cycle by sequestering and solubilizing the GDP-bound form (Moon and Zheng, 2003; Schmidt and Hall, 2002; Zheng, 2001).”
• Rac and Rho GTPases in cancer cell motility control (2010, background): “The GEF family is really large, consisting of over 70 proteins mainly belonging to the Dbl or the Dock families [5,6].”
• Rho GTPases: biochemistry and biology. (2005, background): “This activity is controlled by (a) guanine nucleotide exchange factors (GEFs) that catalyze exchange of GDP for GTP to activate the switch (Schmidt & Hall 2002); (b) GTPaseactivating proteins (GAPs) that stimulate the intrinsic GTPase activity to inactivate the switch (Bernards 2003); and (c)…”