Identification and molecular characterization of the Gα12–Rho guanine nucleotide exchange factor pathway in
            <i>Caenorhabditis elegans</i>

Yau, Douglas M.; Yokoyama, Nobuhiko; Goshima, Yoshio; Siddiqui, Zeba K.; Siddiqui, Shahid; Kozasa, Tohru

doi:10.1073/pnas.2533143100

Cited by 42 publications

(28 citation statements)

References 41 publications

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“…appreciated role of Rho GTPases and the Gα 12/13 -Rho GEF-Rho GTPase mediated pathways in the regulation of neuronal morphogenesis. 59,60 In conclusion, in the present work we have shown that activated Gα 13 as well as Gα 13 coupled GPCR agonists induce proto-Dbl activation of Rho GTPase pathways including the p38 and JNK kinases. This is associated with Gα 13 -mediated proto-Dbl interaction with ezrin at the plasma membrane.…”

Section: Methodssupporting

confidence: 61%

Gα13 Regulation of Proto-Dbl Signaling

Vanni¹,

Mancini²,

Ottaviano³

et al. 2007

Cell Cycle

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Rho family GTPases play important roles in the regulation of intracellular signals induced by activated heterotrimeric G proteins of the α 12/13 family. The α 12/13 subunits activate Rho GTPases through direct binding to a group of Rho guanine nucleotide exchange factors (GEFs) characterized by the presence of a G protein signaling-like (RGL) domain. The Rho GEF proto-Dbl, that does not contain a RGL domain, was also found to link Gα 12/13 signals to Rho. We have explored the effects of activated Gα 13 and Gα 13 -associated G protein-coupled receptor (GPCR) agonists on proto-Dbl regulation. We show that activated Gα 13 , but not Gα 12 or Gα q , induces translocation of proto-Dbl to the cell membrane with consequent enlargement of cell body and membrane ruffling. These effects were evident also when Gα 13 -associated GPCR agonists were used on cells expressing proto-Dbl and were accompanied by the activation of Cdc42 and RhoA GTPases and further downstream effector JNK and p38 kinases. Moreover, we show that both activated Gα 13 and GPCR agonists stimulate proto-Dbl interaction with ezrin to promote ezrin translocation to the plasma membrane. These results suggest a mechanism by which proto-Dbl and its effector pathways are regulated by Gα 13 -mediated signals through association with ezrin.

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Section: Methodssupporting

confidence: 61%

Gα13 Regulation of Proto-Dbl Signaling

Vanni¹,

Mancini²,

Ottaviano³

et al. 2007

Cell Cycle

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“…Previous C. elegans studies also identified GPA-12 (G␣ 12 ) as an activator of p115 RhoGEF and RHO-1 (RhoA) (Yau et al 2003;Hiley et al 2006). Hyperactivating this pathway, which is broadly expressed in C. elegans neurons, increases aldicarb sensitivity and causes exaggerated body movements through its effects on inhibiting DGK-1 (diacylglycerol kinase), to which RHO-1 directly binds McMullan et al 2006).…”

Section: Other Sources Of Rhoa Activation In Regulating Synaptic Signmentioning

confidence: 98%

Trio’s Rho-specific GEF domain is the missing Gα_q effector in C. elegans

Williams¹,

Lutz

Charlie³

et al. 2007

Genes Dev.

148

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The G␣ q pathway is essential for animal life and is a central pathway for driving locomotion, egg laying, and growth in Caenorhabditis elegans, where it exerts its effects through EGL-8 (phospholipase C␤ [PLC␤]) and at least one other effector. To find the missing effector, we performed forward genetic screens to suppress the slow growth and hyperactive behaviors of mutants with an overactive G␣ q pathway. Four suppressor mutations disrupted the Rho-specific guanine-nucleotide exchange factor (GEF) domain of UNC-73 (Trio). The mutations produce defects in neuronal function, but not neuronal development, that cause sluggish locomotion similar to animals lacking EGL-8 (PLC␤). Strains containing null mutations in both EGL-8 (PLC␤) and UNC-73 (Trio RhoGEF) have strong synthetic phenotypes that phenocopy the arrested growth and near-complete paralysis of G␣ q -null mutants. Using cell-based and biochemical assays, we show that activated C. elegans G␣ q synergizes with Trio RhoGEF to activate RhoA. Activated G␣ q and Trio RhoGEF appear to be part of a signaling complex, because they coimmunoprecipitate when expressed together in cells. Our results show that Trio's Rho-specific GEF domain is a major G␣ q effector that, together with PLC␤, mediates the G␣ q signaling that drives the locomotion, egg laying, and growth of the animal.[Keywords: G␣ q ; Trio; Rho; phospholipase C␤; C. elegans] Supplemental material is available at http://www.genesdev.org.

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“…RHGF-1 is a multidomain protein that contains PDZ, RGS (regulator of G protein signaling), C1 (phorbol esters/diacylglycerol binding), DH (Dbl homology), and PH (pleckstrin homology) domains ( Fig. 2A) (26,27). The GTP exchange activity of RHGF-1 resides in the DH domain.…”

Section: Significancementioning

confidence: 99%

RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly

Chen

Lee

Liao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurons remodel their connectivity in response to various insults, including microtubule disruption. How neurons sense microtubule disassembly and mount remodeling responses by altering genetic programs in the soma are not well defined. Here we show that in response to microtubule disassembly, the Caenorhabditis elegans PLM neuron remodels by retracting its synaptic branch and overextending the primary neurite. This remodeling required RHGF-1, a PDZ-Rho guanine nucleotide exchange factor (PDZ-RhoGEF) that was associated with and inhibited by microtubules. Independent of the myosin light chain activation, RHGF-1 acted through Rho-dependent kinase LET-502/ROCK and activated a conserved, retrograde DLK-1 MAPK (DLK-1/dual leucine zipper kinase) pathway, which triggered synaptic branch retraction and overgrowth of the PLM neurite in a dose-dependent manner. Our data represent a neuronal remodeling paradigm during development that reshapes the neural circuit by the coordinated removal of the dysfunctional synaptic branch compartment and compensatory extension of the primary neurite.axon retraction | axon regeneration | Rho signaling | DLK | microtubules T he connectivity of neuronal circuits is established first through a highly dynamic phase of addition or elimination of axon branches and synapses, followed by a maintenance phase in which axon and dendritic branches show remarkable stability during the lifetime of postmitotic neurons. Disruption of neuronal circuits elicits remodeling responses that eliminate dysfunctional neurites or synapses and may stimulate the regeneration of injured axons. To enable these remodeling responses, neurons need to sense the insults and signal to the effectors that execute either retraction or extension of the neuronal structures. A well-studied effector for neuronal remodeling is the dual leucine-zipper kinase DLK, whose activation is required for both Wallerian degeneration and axon regeneration after injury, depending on the species and contexts examined (1-4). The DLK protein level is primarily controlled by proteasomal turnover that depends on Highwire/RPM-1, a ubiquitin E3 ligase that targets DLK for degradation (5). The Caenorhabditis elegans DLK, DLK-1, is activated by calcium influx during axon injury that triggers the dissociation of an inhibitory DLK-1 isoform (6). A recent report suggests that C. elegans dlk-1 is a direct transcriptional target of the FoxO transcription factor DAF-16 in axon regeneration (7). Despite the extensive characterization of DLK, little is known about how neurons sense various insults and translate them into DLK-activating signals.Microtubules are a major neuronal cytoskeleton component that shapes and maintains synapses and axons (8, 9). Mutations in Ankyrin and α-spectrin, two membrane skeletal proteins that organize microtubules at presynaptic sites, triggered synaptic bouton shrinkage and axon terminal retraction at Drosophila neuromuscular junction, highlighting the central importance of microtubules in the maintenance of synapses and axon b...

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Identification and molecular characterization of the Gα12–Rho guanine nucleotide exchange factor pathway in Caenorhabditis elegans

Cited by 42 publications

References 41 publications

Gα13 Regulation of Proto-Dbl Signaling

Gα13 Regulation of Proto-Dbl Signaling

Trio’s Rho-specific GEF domain is the missing Gα_q effector in C. elegans

RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly

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Identification and molecular characterization of the Gα12–Rho guanine nucleotide exchange factor pathway in Caenorhabditis elegans

Cited by 42 publications

References 41 publications

G&alpha;13 Regulation of Proto-Dbl Signaling

G&alpha;13 Regulation of Proto-Dbl Signaling

Trio’s Rho-specific GEF domain is the missing Gαq effector in C. elegans

RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly

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Product

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Gα13 Regulation of Proto-Dbl Signaling

Gα13 Regulation of Proto-Dbl Signaling

Trio’s Rho-specific GEF domain is the missing Gα_q effector in C. elegans