A Rac-cGMP Signaling Pathway

Guo, Di; Ya, Tan; Wang, Dawei; Madhusoodanan, K. S.; Zheng, Yi; Maack, Thomas; Zhang, J. Jillian; Huang, Xin‐Yun

doi:10.1016/j.cell.2006.11.048

Cited by 99 publications

(117 citation statements)

References 44 publications

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“…These observations identify a function of cGKI signaling in the regulation of erythrocyte survival and support the emerging concept that pathways via NO, cGMP, and cGKI stimulate growth and survival in a number of cell types in vivo (55)(56)(57)(58).…”

Section: Figsupporting

confidence: 55%

Anemia and splenomegaly in cGKI-deficient mice

Föller

Feil²,

Ghoreschi³

et al. 2008

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

133

115

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To explore the functional significance of cGMP-dependent protein kinase type I (cGKI) in the regulation of erythrocyte survival, gene-targeted mice lacking cGKI were compared with their control littermates. By the age of 10 weeks, cGKI-deficient mice exhibited pronounced anemia and splenomegaly. Compared with control mice, the cGKI mutants had significantly lower red blood cell count, packed cell volume, and hemoglobin concentration. Anemia was associated with a higher reticulocyte number and an increase of plasma erythropoietin concentration. The spleens of cGKI mutant mice were massively enlarged and contained a higher fraction of Ter119 ؉ erythroid cells, whereas the relative proportion of leukocyte subpopulations was not changed. The Ter119 ؉ cGKI-deficient splenocytes showed a marked increase in annexin V binding, pointing to phosphatidylserine (PS) exposure at the outer membrane leaflet, a hallmark of suicidal erythrocyte death or eryptosis. Compared with control erythrocytes, cGKI-deficient erythrocytes exhibited in vitro a higher cytosolic Ca 2؉ concentration, a known trigger of eryptosis, and showed increased PS exposure, which was paralleled by a faster clearance in vivo. Together, these results identify a role of cGKI as mediator of erythrocyte survival and extend the emerging concept that cGMP/cGKI signaling has an antiapoptotic/prosurvival function in a number of cell types in vivo.apoptosis ͉ Ca2ϩ channels ͉ phosphatidylserine ͉ spleen N itric oxide (NO) has been shown to be a powerful regulator of cell survival (1, 2). Depending on the source or concentration of NO and the influence of additional regulators, NO may stimulate or inhibit apoptosis (3). NO exerts its effects in part through S-nitrosylation of target proteins. However, the effect of NO donors on Ca 2ϩ -induced phosphatidylserine (PS) exposure, a hallmark of apoptosis, could be mimicked by cGMP analogs (4), suggesting the involvement of soluble guanylyl cyclase, cGMP, and cGMP-dependent protein kinase type I (cGKI), a well known signaling cascade downstream of NO (5, 6).Recent studies indicated that erythroid cells possess a functional NO/cGMP pathway (7-9), which may be involved in the regulation of eryptosis, the suicidal death of erythrocytes (10). Erythrocyte cGMP production might also be stimulated by NO generated in the endothelium. The cGKI can also be activated independent of cGMP in response to oxidative stress (11). Eryptosis may follow osmotic shock, energy depletion, and oxidative stress (10), which activate Ca 2ϩ -permeable cation channels (12). Subsequent Ca 2ϩ entry leads to activation of Ca 2ϩ -sensitive K ϩ channels, exit of KCl with osmotically obliged water, and thus cell shrinkage (13). In addition, Ca 2ϩ entry triggers Ca 2ϩ -sensitive scrambling of the cell membrane (14, 15) with subsequent exposure of PS at the erythrocyte surface (12). Cell membrane scrambling may further be triggered by ceramide (16) and activation of protein kinase C (17). PS-exposing erythrocytes bind to PS receptors (18) and are recognized, ...

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Section: Figsupporting

confidence: 55%

Anemia and splenomegaly in cGKI-deficient mice

Föller

Feil²,

Ghoreschi³

et al. 2008

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

133

115

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“…Constructs were transfected into CHO cells and the GC activity assay was performed as previously described (Guo et al 2007(Guo et al , 2009). Cells were cultured in growth medium to 95% confluency and were washed in a buffer containing 50 mM NH 4 Ac and 200 mM sucrose pH 7 (plus 1 mM IBMX).…”

Section: Heterologous Expression and Gc Assays Of Gc Proteins In Tissmentioning

confidence: 99%

“…A conceptually similar reconstitution experiment in the AWC olfactory neurons resulted in no rescue, consistent with the fact that the AWC dendritic endings are not exposed to the environment (data not shown). Taken together, the ASI-specific reconstitution experiment provides further support for the hypothesis that GCY-4 and GCY-22 may collaborate, possibly as a heterodimer, to confer a chemosensory function.Lastly, we attempted to measure salt-inducible GCY protein activity in heterologous cell culture aassys (Guo et al 2007(Guo et al , 2009). We co-expressed GCY-4 and GCY-22 proteins in Chinese hamster ovary (CHO) cells and tested whether guanylyl cyclase activity could be directly stimulated by bromide, chloride, or sodium.…”

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confidence: 99%

Defining Specificity Determinants of cGMP Mediated Gustatory Sensory Transduction inCaenorhabditis elegans

et al. 2013

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Cyclic guanosine monophosphate (cGMP) is a key secondary messenger used in signal transduction in various types of sensory neurons. The importance of cGMP in the ASE gustatory receptor neurons of the nematode Caenorhabditis elegans was deduced by the observation that multiple receptor-type guanylyl cyclases (rGCs), encoded by the gcy genes, and two presently known cyclic nucleotide-gated ion channel subunits, encoded by the tax-2 and tax-4 genes, are essential for ASE-mediated gustatory behavior. We describe here specific mechanistic features of cGMP-mediated signal transduction in the ASE neurons. First, we assess the specificity of the sensory functions of individual rGC proteins. We have previously shown that multiple rGC proteins are expressed in a left/right asymmetric manner in the functionally lateralized ASE neurons and are required to sense distinct salt cues. Through domain swap experiments among three different rGC proteins, we show here that the specificity of individual rGC proteins lies in their extracellular domains and not in their intracellular, signal-transducing domains. Furthermore, we find that rGC proteins are also sufficient to confer salt sensory responses to other neurons. Both findings support the hypothesis that rGC proteins are salt receptor proteins. Second, we identify a novel, likely downstream effector of the rGC proteins in gustatory signal transduction, a previously uncharacterized cyclic nucleotide-gated (CNG) ion channel, encoded by the che-6 locus. che-6 mutants show defects in gustatory sensory transduction that are similar to defects observed in animals lacking the tax-2 and tax-4 CNG channels. In contrast, thermosensory signal transduction, which also requires tax-2 and tax-4, does not require che-6, but requires another CNG, cng-3. We propose that CHE-6 may form together with two other CNG subunits, TAX-2 and TAX-4, a gustatory neuron-specific heteromeric CNG channel complex.T HE identification and subsequent molecular characterization of mutant Caenorhabditis elegans strains defective in sensing specific environmental parameters has revealed many components of signal transduction pathways in sensory neurons (Bargmann 2006;Sengupta 2007). Among the genes identified by mutant analysis are those coding for several distinct cyclic guanosine monophosphate (cGMP)-generating guanylyl cyclases (GCs), cGMP-dependent protein kinase, as well as cyclic nucleotide-gated (CNG) channels (Coburn and Bargmann 1996;Komatsu et al. 1996;Birnby et al. 2000;Daniels et al. 2000; L'Etoile and Bargmann 2000;Cheung et al. 2004;Gray et al. 2004;Inada et al. 2006;Pradel et al. 2007;Ortiz et al. 2009). These genes are expressed in different types of sensory neurons and are required for sensation of odorants, gustatory cues, temperature, bacterial pathogens, and ambient oxygen levels. cGMP has therefore emerged as a key signal transducer for various sensory modalities.While the cGMP dependence of many sensory systems is now well established, sensory receptors that trigger the cGMPdependent s...

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“…Boyden Chamber Cell Migration Assay-Cell migration was assayed using Boyden chambers (8.0 m pore size polyethylene terephthalate membrane, FALCON cell culture insert (BectonDickinson)) (9,(13)(14)(15). Cells were starved for 15 h, trypsinized, and counted.…”

Section: Methodsmentioning

confidence: 99%

Atypical Protein Kinase Cλ Is Critical for Growth Factor Receptor-induced Dorsal Ruffle Turnover and Cell Migration

Xing

Wang

Guo

et al. 2013

Journal of Biological Chemistry

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Background: Growth factors induce actin cytoskeletal reorganization and cell migration in fibroblast cells. Results: Genetic inactivation of aPKC in mouse embryonic fibroblast cells inhibits PDGF-induced dorsal ruffle turnover and cell migration. Conclusion: Our results demonstrate a critical role for aPKC in PDGF-induced dorsal ruffle turnover and cell migration. Significance: These data will advance our understanding of the regulation of cell morphology induced by growth factors.

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A Rac-cGMP Signaling Pathway

Cited by 99 publications

References 44 publications

Anemia and splenomegaly in cGKI-deficient mice

Anemia and splenomegaly in cGKI-deficient mice

Defining Specificity Determinants of cGMP Mediated Gustatory Sensory Transduction inCaenorhabditis elegans

Atypical Protein Kinase Cλ Is Critical for Growth Factor Receptor-induced Dorsal Ruffle Turnover and Cell Migration

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