Members of the protein superfamily of small guanosine triphosphatases, also known as small GTPases, small G-proteins, or the Ras superfamily, are involved in nearly every aspect of cell biology. Small GTPases are tightly regulated molecular switches that make binary on/off decisions through controlled loading of GTP (activation) and hydrolysis of GTP to GDP (inactivation). Small GTPases typically function as nodal points that integrate broad upstream regulatory inputs and disseminate broad effector outputs. The superfamily comprises five families that are conserved across eukaryotes: Ras, Rho, Rab, Arf, and Ran. Each family, besides Ran, has radiated functionally since our last common ancestor with fungi, and certain subfamilies persist throughout metazoa. The double genome duplication leading to vertebrates resulted in two to four genes for many subfamilies, plus some novel mammalian additions. Here we discuss general principles of small GTPase biology, survey the C. elegans complement of small GTPases and how they compare to their mammalian counterparts, and note atypical nematode members that do not fall into discrete subfamilies. We do not discuss the multitude of other proteins with catalytic guanosine triphosphatase domains that fall outside the small GTPase/Ras superfamily.

Background: The founding member of the EMAP-like protein family is the Echinoderm Microtubule-Associated Protein (EMAP), so-named for its abundance in sea urchin, starfish, and sand dollar eggs. The EMAP-like protein family has five members in mammals (EML1 through EML5) and only one in both Drosophila (ELP-1) and C. elegans (ELP-1). Biochemical studies of sea urchin EMAP and vertebrate EMLs implicate these proteins in the regulation of microtubule stability. So far, however, the physiological function of this protein family remains unknown. Results: We examined the expression pattern of C. elegans ELP-1 by means of transgenic gene expression in living embryos and adults, and by immunolocalization with an ELP-1-specific antibody in fixed tissues. In embryos, ELP-1 is expressed in the hypodermis. In larvae and adults, ELP-1 is expressed in the body wall, spermatheca and vulval muscles, intestine, and hypodermal seam cells. In muscle, ELP-1 is associated with adhesion complexes near the cell surface and is bound to a criss-crossing network of microtubules in the cytoplasm. ELP-1 is also expressed in a subset of mechanoreceptor neurons, including the ray neurons in the male tail, microtubule-rich touch receptor neurons, and the six ciliated IL1 neurons. This restricted localization in the nervous system implies that ELP-1 plays a role in mechanotransmission. Consistent with this idea, decreasing ELP-1 expression decreases sensitivity to gentle touch applied to the body wall. Conclusion: These data imply that ELP-1 may play an important role during the transmission of forces and signals between the body surface and both muscle cells and touch receptor neurons.

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.

The mechanisms linking guidance receptors to cytoskeletal dynamics in the growth cone during axon extension remain mysterious. The Rho-family GTPases Rac and CDC-42 are key regulators of growth cone lamellipodia and filopodia formation, yet little is understood about how these molecules interact in growth cone outgrowth or how the activities of these molecules are regulated in distinct contexts. UNC-73/Trio is a well-characterized Rac GTP exchange factor in Caenorhabditis elegans axon pathfinding, yet UNC-73 does not control CED-10/Rac downstream of UNC-6/Netrin in attractive axon guidance. Here we show that C. elegans TIAM-1 is a Rac-specific GEF that links CDC-42 and Rac signaling in lamellipodia and filopodia formation downstream of UNC-40/DCC. We also show that TIAM-1 acts with UNC-40/DCC in axon guidance. Our results indicate that a CDC-42/TIAM-1/Rac GTPase signaling pathway drives lamellipodia and filopodia formation downstream of the UNC-40/DCC guidance receptor, a novel set of interactions between these molecules. Furthermore, we show that TIAM-1 acts with UNC-40/DCC in axon guidance, suggesting that TIAM-1 might regulate growth cone protrusion via Rac GTPases in response to UNC-40/DCC. Our results also suggest that Rac GTPase activity is controlled by different GEFs in distinct axon guidance contexts, explaining how Rac GTPases can specifically control multiple cellular functions. Axons extend great distances to make precise synaptic connections in the developing nervous system. Axons are guided to their targets by the growth cone, a dynamic structure at the axon distal tip that senses extracellular cues telling the axon where to go. In response to guidance cues, growth cones alter their shape and motility resulting in outgrowth and turning. The cytoskeleton (actin and microtubules) underlies growth cone motility and guidance. The signaling mechanisms linking guidance receptors to cytoskeletal change remain mysterious. Here, we define a new signaling mechanism downstream of the guidance receptor UNC-40/DCC involving the GTPases CDC-42 and Rac, which have long been known to control growth cone protrusion. We show that CDC-42 and Rac act in a linear pathway in axon guidance; CDC-42 acts upstream of the GTPase regulatory molecule TIAM-1, which is a GTP exchange factor specific for Rac and which activates Rac signaling. We also show that TIAM-1 acts with UNC-40/DCC signaling in protrusion and axon guidance. Our results imply that Rac GTPase function in axon guidance is complex and that distinct GEFs (TIAM-1 and UNC-73/Trio) might control Rac GTPases in different aspects of axon guidance.

Worms yield opioid receptor insight: The µ-opioid receptor (MOR) is the target of pain-reducing drugs, including morphine and the potent synthetic opioid fentanyl. Better understanding of the receptor system is needed to suppress potentially deadly side effects and manage addiction potential. Wang et al. used a screen in the worm Caenorhabditis elegans to find genes that influenced MOR function (see the Perspective by Mercer Lindsay and Scherrer). They found another receptor called GPR139, loss of which enhanced effects of morphine in mice but reduced withdrawal effects. GPR139 could be a target to improve safety or efficacy of opioid therapy. Science , this issue p. 1267 ; see also p. 1246