-
[
Small GTPases,
2013]
The Rho family of GTPases (members of the Ras superfamily) are best known for their roles in regulating cytoskeletal dynamics. It is also well established that misregulation of Rho proteins contributes to tumorigenesis and metastasis. Unlike Ras proteins, which are frequently mutated in cancer (around 30%), Rho proteins themselves are generally not found to be mutated in cancer. Rather, misregulation of Rho activity in cancer was thought to occur by overexpression of these proteins or by misregulation of molecules that control Rho activity, such as activation or overexpression of GEFs and inactivation or loss of GAPs or GDIs. Recent studies, enabled by next-generation tumor exome sequencing, report activating point mutations in Rho GTPases as driver mutations in melanoma, as well as breast, and head and neck cancers. The Rac1(P29L) mutation identified in these tumor studies was previously identified by our lab as an activating Rac mutation in C. elegans neuronal development, highlighting the conserved nature of this mutation. Furthermore, this finding supports the relevance of studying Rho GTPases in model organisms such as C. elegans to study the mechanisms that underlie carcinogenesis. This review will describe the recent findings that report activating Rho mutations in various cancer types, moving Rho GTPases from molecules misregulated in cancer to mutagenic targets that drive tumorigenesis.
-
[
Dev Cell,
2002]
The central spindle is important for the completion of cytokinesis. Genetic and biochemical approaches have identified a tetrameric complex, made up of a mitotic kinesin-like protein and a Rho-GTPase activating protein, that mediates central spindle assembly.
-
[
Dev Cell,
2002]
In migrating cells, Rho family GTPases and their effectors play a central role in polarizing and in organizing the actin and microtubule cytoskeletons. A study by Fukata et al. in the June 28th issue of Cell now shows that the Rac1/Cdc42 effector IQGAP1 captures microtubules by binding to CLIP170.
-
[
Development,
2007]
The symmetry-breaking event during polarization of C. elegans embryos is an asymmetric rearrangement of the acto-myosin network, which dictates cell polarity through the differential recruitment of PAR proteins. The sperm-supplied centrosomes are required to initiate this cortical reorganization. Several questions about this event remain unanswered: how is the acto-myosin network regulated during polarization and how does acto-myosin reorganization lead to asymmetric PAR protein distribution? As we discuss, recent studies show that C. elegans embryos use two GTPases, RHO-1 and CDC-42, to regulate these two steps in polarity establishment. Although RHO-1 and CDC-42 control distinct aspects of polarization, they function interdependently to regulate polarity establishment in C. elegans embryos.
-
[
Cell,
2005]
Biological rhythms with periods of less than a day are physiologically important but poorly understood. In this issue of Cell, Norman, Maricq, and colleagues (Norman et al., 2005) show that VAV-1, a guanine nucleotide exchange factor for Rho-family GTPases, is necessary for three rhythmic behaviors in the nematode Caenorhabditis elegans: feeding, defecation, and ovulation.
-
[
WormBook,
2006]
Small GTPases of the Ras superfamily are key regulators of diverse cellular and developmental events, including differentiation, cell division, vesicle transport, nuclear assembly, and control of the cytoskeleton. The C. elegans genome encodes 56 members of the major Ras GTPase subfamilies, including the Ras/Ral/Rap family, the Rho family, the Rab family, Ran, and the Arf/Sar family. Studies in C. elegans have shown that Ras/Rap family members control cell fate specification and differentiation; Rho GTPases control morphogenesis and actin dynamics, including axon pathfinding and cell migration; Rab GTPases control synaptic vesicle trafficking and release and gene expression responses in innate immunity; the Ran GTPase controls nuclear import/export, nuclear reassembly after mitosis, and kinetechore association with microtubules; and Arf/Sar GTPases control morphogenesis and microtubule organization and possibly cilia development. Functions for many of the small GTPases remain to be discovered, and continuing studies in C. elegans will elucidate the roles of these molecules in animal development.
-
[
Cold Spring Harb Perspect Biol,
2009]
The nematode worm Caenorhabditis elegans has produced a wellspring of insights into mechanisms that govern cellular symmetry breaking during animal development. Here we focus on two highly conserved systems that underlie many of the key symmetry-breaking events that occur during embryonic and larval development in the worm. One involves the interplay between Par proteins, Rho GTPases, and the actomyosin cytoskeleton and mediates asymmetric cell divisions that establish the germline. The other uses elements of the Wnt signaling pathway and a highly reiterative mechanism that distinguishes anterior from posterior daughter cell fates. Much of what we know about these systems comes from intensive study of a few key events-Par/Rho/actomyosin-mediated polarization of the zygote in response to a sperm-derived cue and the Wnt-mediated induction of endoderm at the four-cell stage. However, a growing body of work is revealing how C. elegans exploits elements/variants of these systems to accomplish a diversity of symmetry-breaking tasks throughout embryonic and larval development.
-
[
Essays Biochem,
2000]
Myosins constitute a large superfamily of F-actin-based motor proteins found in many organisms from yeast to humans. A phylogenetic comparison of their head sequences has allowed them to be grouped into 15 different classes. Unconventional myosins can be monomeric or dimeric, but are thought not to form filaments, unlike conventional myosin. The double-headed class-V myosins are good candidates for transporting vesicles, organelles and (mRNA) particles along actin filaments. Class-I myosins are involved in membrane dynamics and actin organization at the cell cortex, thus affecting cell migration, endocytosis, pinocytosis and phagocytosis. A class-III myosin from Drosophila is required for phototransduction and maintenance of the rhabdomere. Class-IX myosins negatively regulate the small G-protein Rho, a signalling molecule that regulates the organization of the actin cytoskeleton. Protein kinases that are regulated by members of the Rho small G-protein family regulate the motor activities of different myosins.
-
[
Cell Signal,
2010]
Dock180-related proteins are genetically conserved from Drosophila and C. elegans to mammals and are atypical types of guanine-nucleotide exchange factors (GEFs) for Rac and/or Cdc42 of small GTPases of the Rho family. Eleven members of the family occur in mammalian cells, each playing key roles in many aspects of essential cellular functions such as regulation of cytoskeletal organization, phagocytosis, cell migration, polarity formation, and differentiation. This review will summarize the newly accumulated findings concerning the Dock180-related proteins' molecular and cellular functions, emphasizing the roles of these proteins in neuronal cells and glial cells as well as their interactions in the central and peripheral nervous systems.
-
[
FEBS Lett,
2002]
Phospholipase D1 and D2 (PLD1, PLD2) both have PX and PH domains in their N-terminal regions with these inositol lipid binding domains playing key roles in regulating PLD activity and localisation. The activity of PLD1 is also regulated by protein kinase C and members of the Rho and Arf families of GTPases. Each of these proteins binds to unique sites; however, there appears to be little in vitro discrimination between individual family members. In agonist-stimulated cells, however, there is specificity, with, for example in RBL-2H3 cells, antigen stimulating the activation of PLD1 by association with Arf6, Rac1 and protein kinase Calpha. PLD2 appears to be less directly regulated by GTPases and rather is primarily controlled through interaction with phosphatidylinositol 4-phosphate 5-kinase that generates the activating phosphatidylinositol 4,5-bisphosphate.