The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Paola Bruni - One of the best experts on this subject based on the ideXlab platform.
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the wd40 repeat protein WDR36 orchestrates sphingosine kinase 1 recruitment and phospholipase c β activation by gq coupled receptors
Biochimica et Biophysica Acta, 2020Co-Authors: Kira Blankenbach, Gennaro Bruno, Enrico Wondra, Anna Katharina Spohner, Natalie Judith Aster, Hans Vienken, Sandra Trautmann, Nerea Ferreiros, Thomas Wieland, Paola BruniAbstract:Abstract Sphingosine kinases (SphK) catalyse the formation of sphingosine-1-phosphate (S1P) and play important roles in the cardiovascular, nervous and immune systems. We have shown before that Gq-coupled receptors induce a rapid and long-lasting translocation of SphK1 to the plasma membrane and cross-activation of S1P receptors. Here, we further addressed Gq regulation of SphK1 by analysing the influence of the WD40 repeat protein, WDR36. WDR36 has been described as a scaffold tethering Gαq to phospholipase C (PLC)-β and the thromboxane A2 receptor-β (TPβ receptor). Overexpression of WDR36 in HEK-293 cells enhanced TPβ receptor-induced inositol phosphate production, as reported (Cartier et al. 2011), but significantly attenuated inositol phosphate production induced by muscarinic M3 and bradykinin B2 receptors. In agreement with its effect on PLCβ, WDR36 augmented TPβ receptor-induced [Ca2+]i increases. Surprisingly, WDR36 also augmented M3 receptor-induced [Ca2+]i increases, which was due to increased Ca2+ mobilization while the Ca2+ content of thapsigargin-sensitive stores remained unaltered. Interestingly, overexpression of WDR36 significantly delayed SphK1 translocation by Gq-coupled M3, B2 and H1 receptors in HEK-293 cells, while TPβ receptor-induced SphK1 translocation was generally slow and not altered by WDR36 in these cells. Finally, in C2C12 myoblasts, overexpression of WDR36 delayed SphK1 translocation induced by B2 receptors. It is concluded that WDR36 reduces signalling of Gq-coupled receptors other than TPβ towards PLC and SphK1, most likely by scavenging Gαq and PLCβ. Our results support a role of WDR36 in orchestration of Gq signalling complexes, and might help to functionally unravel its genetic association with asthma and allergy.
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The WD40 repeat protein, WDR36, orchestrates sphingosine kinase-1 recruitment and phospholipase C-β activation by Gq-coupled receptors
Biochimica et Biophysica Acta, 2020Co-Authors: Kira Blankenbach, Gennaro Bruno, Enrico Wondra, Anna Katharina Spohner, Natalie Judith Aster, Hans Vienken, Sandra Trautmann, Nerea Ferreiros, Thomas Wieland, Paola BruniAbstract:Sphingosine kinases (SphK) catalyse the formation of sphingosine-1-phosphate (S1P) and play important roles in the cardiovascular, nervous and immune systems. We have shown before that Gq-coupled receptors induce a rapid and long-lasting translocation of SphK1 to the plasma membrane and cross-activation of S1P receptors. Here, we further addressed Gq regulation of SphK1 by analysing the influence of the WD40 repeat protein, WDR36. WDR36 has been described as a scaffold tethering Galphaq to phospholipase C (PLC)-beta and the thromboxane A2 receptor-beta (TPbeta receptor). Overexpression of WDR36 in HEK-293 cells enhanced TPbeta receptor-induced inositol phosphate production, as reported (Cartier et al. 2011), but significantly attenuated inositol phosphate production induced by muscarinic M3 and bradykinin B2 receptors. In agreement with its effect on PLCbeta, WDR36 augmented TPbeta receptor-induced [Ca(2+)]i increases. Surprisingly, WDR36 also augmented M3 receptor-induced [Ca(2+)]i increases, which was due to increased Ca(2+) mobilization while the Ca(2+) content of thapsigargin-sensitive stores remained unaltered. Interestingly, overexpression of WDR36 significantly delayed SphK1 translocation by Gq-coupled M3, B2 and H1 receptors in HEK-293 cells, while TPbeta receptor-induced SphK1 translocation was generally slow and not altered by WDR36 in these cells. Finally, in C2C12 myoblasts, overexpression of WDR36 delayed SphK1 translocation induced by B2 receptors. It is concluded that WDR36 reduces signalling of Gq-coupled receptors other than TPbeta towards PLC and SphK1, most likely by scavenging Galphaq and PLCbeta. Our results support a role of WDR36 in orchestration of Gq signalling complexes, and might help to functionally unravel its genetic association with asthma and allergy.
Luis Fernandezvega - One of the best experts on this subject based on the ideXlab platform.
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WDR36 and p53 gene variants and susceptibility to primary open angle glaucoma analysis of gene gene interactions
Investigative Ophthalmology & Visual Science, 2011Co-Authors: Cristina Blancomarchite, Francisco Sanchezsanchez, Mariapilar Lopezgarrido, Mercedes Inigezdeonzono, Francisco Lopezmartinez, Enrique Lopezsanchez, Lydia Alvarez, Pedropablo Rodriguezcalvo, Carmen Mendezhernandez, Luis FernandezvegaAbstract:Purpose. To investigate the role of WDR36 and P53 sequence variations in POAG susceptibility.
Michael A Walter - One of the best experts on this subject based on the ideXlab platform.
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Co-variation of STI1 and WDR36/UTP21 alters cell proliferation in a glaucoma model
Molecular Vision, 2011Co-Authors: Tim Footz, Stephane Dubois, Vincent Raymond, M Sarfarazi, Michael A WalterAbstract:Molecular Ophthalmic Genetics Laboratory, University of Connecticut Health Center,Farmington, CTPurpose: To investigate the role of multigenic variation in primary open-angle glaucoma (POAG) involving the rRNAprocessing gene WD repeat domain 36 (WDR36).Methods: We examined the heat shock protein 70/90 (HSP70/90)-organizing co-chaperone stress-induced-phosphoprotein 1 (STI1) as a potential co-modifying gene in glaucoma patients found to harbor WDR36 amino acidvariation. The STI1 gene was sequenced and its POAG-associated amino acid variant K434R, as well as the singlenucleotide polymorphism (SNP) P173T, were tested for functional defects in a yeast model system previously used tocharacterize WDR36 variants (using the homologous yeast gene U3 protein 21 [UTP21]).Results: A POAG patient heterozygous for the WDR36 variant L25P was discovered to also carry the STI1 variant K434Rin a heterozygous state. Variant K434R, located at an evolutionarily-conserved site, was not found in a pool of clinically-examined individuals lacking WDR36 variation which included 55 normal controls and 20 patients with normal tensionglaucoma (NTG). STI1 (K434R) and the homologous yeast variant K470R were able to rescue yeast growth-inhibitionby the HSP90-inhibitor radicicol. Double mutant haploid strains expressing human STI1 (K434R) and recombinant yeastUTP21 variants did not have significantly different levels of 18S rRNA from the corresponding hSTI1 (WT) strains.However, specific double mutant K434R strains exhibited significantly slower culture growth at 37 °C. Double mutantP173T strains also displayed altered growth rates at 37 °C.Conclusions: STI1 variation does not play a significant direct role in the genetics of POAG. However, as previously foundfor the STI1 null allele, non-synonymous variants of human STI1 confer growth dysregulation in the context of specificyeast UTP21 mutations and heat stress. Based on the genetic association of two co-heterozygous STI1 and WDR36 variantsin a POAG patient and the functional analyses performed in a model system for basic eukaryotic cellular processes, theseexperiments point to a conserved molecular pathway involving STI1 and WDR36.
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co variation of sti1 and WDR36 utp21 alters cell proliferation in a glaucoma model
Molecular Vision, 2011Co-Authors: Tim Footz, Stephane Dubois, Vincent Raymond, M Sarfarazi, Michael A WalterAbstract:Molecular Ophthalmic Genetics Laboratory, University of Connecticut Health Center,Farmington, CTPurpose: To investigate the role of multigenic variation in primary open-angle glaucoma (POAG) involving the rRNAprocessing gene WD repeat domain 36 (WDR36).Methods: We examined the heat shock protein 70/90 (HSP70/90)-organizing co-chaperone stress-induced-phosphoprotein 1 (STI1) as a potential co-modifying gene in glaucoma patients found to harbor WDR36 amino acidvariation. The STI1 gene was sequenced and its POAG-associated amino acid variant K434R, as well as the singlenucleotide polymorphism (SNP) P173T, were tested for functional defects in a yeast model system previously used tocharacterize WDR36 variants (using the homologous yeast gene U3 protein 21 [UTP21]).Results: A POAG patient heterozygous for the WDR36 variant L25P was discovered to also carry the STI1 variant K434Rin a heterozygous state. Variant K434R, located at an evolutionarily-conserved site, was not found in a pool of clinically-examined individuals lacking WDR36 variation which included 55 normal controls and 20 patients with normal tensionglaucoma (NTG). STI1 (K434R) and the homologous yeast variant K470R were able to rescue yeast growth-inhibitionby the HSP90-inhibitor radicicol. Double mutant haploid strains expressing human STI1 (K434R) and recombinant yeastUTP21 variants did not have significantly different levels of 18S rRNA from the corresponding hSTI1 (WT) strains.However, specific double mutant K434R strains exhibited significantly slower culture growth at 37 °C. Double mutantP173T strains also displayed altered growth rates at 37 °C.Conclusions: STI1 variation does not play a significant direct role in the genetics of POAG. However, as previously foundfor the STI1 null allele, non-synonymous variants of human STI1 confer growth dysregulation in the context of specificyeast UTP21 mutations and heat stress. Based on the genetic association of two co-heterozygous STI1 and WDR36 variantsin a POAG patient and the functional analyses performed in a model system for basic eukaryotic cellular processes, theseexperiments point to a conserved molecular pathway involving STI1 and WDR36.
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glaucoma associated WDR36 variants encode functional defects in a yeast model system
Human Molecular Genetics, 2009Co-Authors: Tim Footz, Jill L Johnson, Stephane Dubois, Nicolas Boivin, Vincent Raymond, Michael A WalterAbstract:Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. POAG is associated with a characteristic progression of changes to ocular morphology and degeneration at the optic nerve head with the loss of visual fields. Physical mapping efforts identified genomic loci in which to search for causative POAG gene mutations. WDR36, at locus GLC1G, was initially identified as a gene with a low frequency of non-synonymous sequence variations that were exclusive to adult-onset POAG patients. It has since been shown that rare WDR36 sequence variants are also present in the normal population at similarly low frequencies. The lack of a consistent genotype:phenotype correlation prompted us to investigate the functional consequences of WDR36 sequence variations. WDR36 is involved in rRNA processing, a critical step in ribosome biogenesis, and is very similar to yeast Utp21p which is a member of the small subunit (SSU) processome complex responsible for maturation of 18S rRNA. We, therefore, developed a yeast model system to test the functional and phenotypic consequences of POAG-associated sequence variants introduced into UTP21. Alone, the POAG variants did not produce any significant defects in cell viability or rRNA processing. However, when combined with disruption of STI1 (which synthetically interacts with UTP21), 5 of the 11 tested variants had increased or decreased cell viability which corresponded to reduced or elevated levels of pre-rRNA, respectively. These results demonstrate that, in the correct genetic background, WDR36 sequence variants can lead to an altered cellular phenotype, supporting the theory that WDR36 participates in polygenic forms of glaucoma.
Chi Pui Pang - One of the best experts on this subject based on the ideXlab platform.
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detection of mutations in myoc optn ntf4 WDR36 and cyp1b1 in chinese juvenile onset open angle glaucoma using exome sequencing
Scientific Reports, 2018Co-Authors: Chukai Huang, Chi Pui Pang, Zhenggen Wu, Yuqian Zheng, Mingzhi ZhangAbstract:Juvenile onset open-angle glaucoma (JOAG) affects patients before 40 years of age, causing high intraocular pressure and severe optic nerve damage. To expand the mutation spectrum of the causative genes in JOAG, with a view to identify novel disease-causing mutations, we investigated MYOC, OPTN, NTF4, WDR36 and CYP1B1 in a cohort of 67 unrelated Chinese JOAG patients. Whole exome sequencing was used to identify possible pathogenic mutations, which were further excluded in normal controls. After sequencing and the use of a database pipeline, as well as predictive assessment filtering, we identified a total of six mutations in three genes, MYOC, OPTN and CYP1B1. Among them, 2 heterozygous mutations in MYOC (c. 1109C > T, p. (P370L); c. 1150G > C, p. (D384H)), 2 heterozygous mutations in OPTN (c. 985A > G, p.(R329G); c. 1481T > G, p. (L494W)) and 2 homozygous mutations in CYP1B1 (c. 1412T > G, p.(I471S); c. 1169G > A, p.(R390H)) were identified as potentially causative mutations. No mutation was detected in NTF4 or WDR36. Our results enrich the mutation spectra and frequencies of MYOC, OPTN and CYP1B1 in JOAG among the Chinese population. Further studies are needed to address the pathogenicity of each of the mutations detected in this study.
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correction of the disease phenotype of myocilin causing glaucoma by a natural osmolyte
Investigative Ophthalmology & Visual Science, 2009Co-Authors: Bo Gong, Chi Pui Pang, Yao Huang, Ningli WangAbstract:PURPOSE. To characterize a novel Asp384Asn (D384N) mutant myocilin (MYOC) that causes juvenile-onset open-angle glaucoma (JOAG) and investigate the correction of mutant phenotype by a natural osmolyte, trimethylamine N-oxide (TMAO). METHODS. A Chinese JOAG family was recruited and genomic DNA was extracted from peripheral blood obtained from 44 family members. Coding regions of the MYOC were sequenced. Two hundred individuals (60 years old) without ocular hypertension or glaucoma were the control subjects. Full-length human wild-type MYOC cDNA was cloned in p3xFLAG-myc-CMV-25 and missense mutation was introduced by site-directed mutagenesis. Transfected human trabecular meshwork cells were treated with small-molecule chemical chaperones. Secreted MYOC was analyzed by combined immunoprecipitation-Western blot analysis. Intracellular myocilin was fractionated into Triton X-100-soluble and insoluble fractions, and analyzed by Western blot analysis. Intracellular aggregate and apoptosis were assayed by immunofluorescence. The effect of TMAO on subcellular myocilin distribution was analyzed by density gradient fractionation, followed by Western blot analysis. RESULTS. A novel c.1150GA change of MYOC was identified. Screening of optineurin, WDR36, and CYP1B1 showed an absence of disease-causing polymorphisms. Mutated D384N myocilin had reduced solubility and was aggregation-prone and nonsecreted. Treatment of transfected cells with TMAO improved the solubility of the D384N mutant, which was corrected for secretion in a dose‐response manner. TMAO reduced the distribution of the D384N mutant in the endoplasmic reticulum (ER), alleviated ER stress, and rescued cells from apoptosis. CONCLUSIONS. The results indicate that TMAO, with chaperoning activity, facilitated the folding and secretion of mutant MYOC. This therapeutic approach assisted by a chemical chaperone can be developed for treating glaucoma. (Invest Ophthalmol Vis Sci. 2009;50:3743‐3749) DOI:10.1167/iovs.08-3151
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different WDR36 mutation pattern in chinese patients with primary open angle glaucoma
Molecular Vision, 2009Co-Authors: Dan Yi Wang, Chingyu Cheng, Wendy Charles Ko, Chi Pui PangAbstract:PURPOSE: To determine the distribution of WD repeat domain 36 (WDR36) sequence variants in Chinese patients with primary open-angle glaucoma (POAG). METHODS: One hundred and thirty-five unrelated POAG patients (82 high tension glaucoma [HTG], 42 normal tension glaucoma [NTG], and 11 juvenile-onset POAG [JOAG] patients) and 77 unrelated controls were recruited. All 23 coding exons and splicing junctions of WDR36 were sequenced using BigDye Terminator v3.1 cycle sequencing kit. Single nucleotide polymorphism (SNP) and haplotype associations were analyzed using PLINK (version 1.04). RESULTS: Nineteen sequence alterations were identified, and eight of them were novel including two novel nonsynonymous SNPs (L240V and I713V). Except the common I264V polymorphism, no other previously reported disease-causing or disease-susceptibility mutations were found. The novel I713V mutation was observed in three (3.7%) patients with HTG. One intronic SNP, IVS5+30C>T (rs10038177), showed significantly higher frequency of minor allele T in HTG patients (16.5%) than in controls (1.3%; Odds ratio [OR]=15.0, p=7.9 x 10(-7), Bonferroni corrected p=1.5 x 10(-5)). Haplotype GTA, which is composed of rs13153937, rs10038177, and rs11241095, was significantly associated with HTG (OR=22.5, p=0.002, Bonferroni corrected p=0.013). Neither the individual SNPs nor haplotypes of WDR36 were associated with NTG or JOAG (Bonferroni corrected p>0.05). CONCLUSIONS: Findings in this study suggest WDR36 to be associated with sporadic HTG but not with NTG or JOAG. Our results also suggest a different mutation pattern of WDR36 in the Chinese population from other ethnic populations.
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Multiple gene polymorphisms analysis revealed a different profile of genetic polymorphisms of primary open-angle glaucoma in northern Chinese.
Molecular Vision, 2009Co-Authors: Sylvia W. Y. Chiang, Chi Pui Pang, Ning Ding, Li Jia Chen, Ningli WangAbstract:Purpose: To evaluate the individual and interactive effects of polymorphisms in the myocilin (MYOC), optineurin (OPTN), WD repeat domain 36 (WDR36), and apolipoprotein E (APOE) genes on primary open-angle glaucoma (POAG) in northern Chinese. Methods: Northern Chinese study subjects, 176 POAG patients and 200 controls, were recruited for screening of the coding exons and splicing regions of MYOC. Five single nucleotide polymorphisms (SNPs) in OPTN (M98K, R545Q, IVS5+38T>G, IVS8-53T>C, and IVS15+10G>A), one SNP in WDR36 (IVS5+30C>T) as well as the APOE promoter and epsilon 2/epsilon 3/epsilon 4 polymorphisms were also examined. Association analysis was performed by using chi(2) analysis. High-order gene-gene interaction was also analyzed using the multifactor dimensionality reduction (MDR) method. Results: In MYOC, 22 variants were identified. Four of them were novel but found in controls only. The missense mutation, Val53Ala, is likely a glaucoma causing mutation, accounting for 0.6% of cases. No individual polymorphism in OPTN, WDR36, or APOE was associated with POAG. MDR analysis identified a best 6-factor model for POAG: MYOC IVS2+35A>G, OPTN Met98Lys, OPTN IVS5+38T>G, OPTN IVS8-53T>C, WDR36 IVS5+30C>T, and APOE -491A>T. Conclusions: The association pattern between the genes, MYOC, OPTN, WDR36, and APOE, and POAG in northern Chinese is different from that of southern Chinese. Disease-causing mutations in MYOC accounted for a small proportion of northern Chinese POAG patients. Common polymorphisms in these genes were not associated with POAG individually but might interactively contribute to the disorder, supporting a polygenic etiology.
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Fine mapping of new glaucoma locus GLC1M and exclusion of neuregulin 2 as the causative gene.
Molecular Vision, 2007Co-Authors: Wendy Charles Ko, Robert Ritch, Dan Yi Wang, Oscar Canlas, Chi Pui PangAbstract:PURPOSE: We recently identified a novel glaucoma locus on 5q22.1-q32, designated as GLC1M, in a family from the Philippines with autosomal dominant juvenile-onset primary open angle glaucoma (JOAG). No mutations in myocilin (MYOC), optineurin (OPTN), and WD-repeat protein 36 (WDR36) were found. Neuregulin 2 (NRG2) is an excellent potential functional as well as positional candidate at GLC1M. The goal of the present study was to evaluate the role of the NRG2 gene in this JOAG family and unrelated JOAG patients and to refine the critical interval for GLC1M. METHODS: Genomic DNA was obtained from 27 family members. All coding exons and splicing sites of NRG2 were screened for sequence alterations by polymerase chain reaction (PCR) and DNA sequencing. A cohort of 92 unrelated JOAG patients and 92 control subjects were genotyped for the three single nucleotide polymorphisms (SNPs) of NRG2 by PCR and DNA sequencing. Haplotype and segregation analyses were performed in the family. Fisher's exact test was used to compare the frequencies of the NRG2 polymorphisms between affected and unaffected subjects in the family and between unrelated JOAG patients and control subjects. RESULTS: Three SNPs were identified: c.98G>A (S33N), IVS3+13A>G (rs889022), and c.1976A>G (G659G). None of them segregated with the JOAG phenotype in this family. No association was found between NRG2 and JOAG in the case-control study (p>0.12). However, further inspection of the haplotypes in the family localized the NRG2 gene telomeric to the disease locus. The critical interval of GLC1M was therefore refined to a region of 28 Mb between D5S2051 and NRG2. CONCLUSIONS: The linkage interval for GLC1M was refined to a smaller region. The NRG2 gene was excluded as the causative gene for JOAG.
Kira Blankenbach - One of the best experts on this subject based on the ideXlab platform.
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the wd40 repeat protein WDR36 orchestrates sphingosine kinase 1 recruitment and phospholipase c β activation by gq coupled receptors
Biochimica et Biophysica Acta, 2020Co-Authors: Kira Blankenbach, Gennaro Bruno, Enrico Wondra, Anna Katharina Spohner, Natalie Judith Aster, Hans Vienken, Sandra Trautmann, Nerea Ferreiros, Thomas Wieland, Paola BruniAbstract:Abstract Sphingosine kinases (SphK) catalyse the formation of sphingosine-1-phosphate (S1P) and play important roles in the cardiovascular, nervous and immune systems. We have shown before that Gq-coupled receptors induce a rapid and long-lasting translocation of SphK1 to the plasma membrane and cross-activation of S1P receptors. Here, we further addressed Gq regulation of SphK1 by analysing the influence of the WD40 repeat protein, WDR36. WDR36 has been described as a scaffold tethering Gαq to phospholipase C (PLC)-β and the thromboxane A2 receptor-β (TPβ receptor). Overexpression of WDR36 in HEK-293 cells enhanced TPβ receptor-induced inositol phosphate production, as reported (Cartier et al. 2011), but significantly attenuated inositol phosphate production induced by muscarinic M3 and bradykinin B2 receptors. In agreement with its effect on PLCβ, WDR36 augmented TPβ receptor-induced [Ca2+]i increases. Surprisingly, WDR36 also augmented M3 receptor-induced [Ca2+]i increases, which was due to increased Ca2+ mobilization while the Ca2+ content of thapsigargin-sensitive stores remained unaltered. Interestingly, overexpression of WDR36 significantly delayed SphK1 translocation by Gq-coupled M3, B2 and H1 receptors in HEK-293 cells, while TPβ receptor-induced SphK1 translocation was generally slow and not altered by WDR36 in these cells. Finally, in C2C12 myoblasts, overexpression of WDR36 delayed SphK1 translocation induced by B2 receptors. It is concluded that WDR36 reduces signalling of Gq-coupled receptors other than TPβ towards PLC and SphK1, most likely by scavenging Gαq and PLCβ. Our results support a role of WDR36 in orchestration of Gq signalling complexes, and might help to functionally unravel its genetic association with asthma and allergy.
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The WD40 repeat protein, WDR36, orchestrates sphingosine kinase-1 recruitment and phospholipase C-β activation by Gq-coupled receptors
Biochimica et Biophysica Acta, 2020Co-Authors: Kira Blankenbach, Gennaro Bruno, Enrico Wondra, Anna Katharina Spohner, Natalie Judith Aster, Hans Vienken, Sandra Trautmann, Nerea Ferreiros, Thomas Wieland, Paola BruniAbstract:Sphingosine kinases (SphK) catalyse the formation of sphingosine-1-phosphate (S1P) and play important roles in the cardiovascular, nervous and immune systems. We have shown before that Gq-coupled receptors induce a rapid and long-lasting translocation of SphK1 to the plasma membrane and cross-activation of S1P receptors. Here, we further addressed Gq regulation of SphK1 by analysing the influence of the WD40 repeat protein, WDR36. WDR36 has been described as a scaffold tethering Galphaq to phospholipase C (PLC)-beta and the thromboxane A2 receptor-beta (TPbeta receptor). Overexpression of WDR36 in HEK-293 cells enhanced TPbeta receptor-induced inositol phosphate production, as reported (Cartier et al. 2011), but significantly attenuated inositol phosphate production induced by muscarinic M3 and bradykinin B2 receptors. In agreement with its effect on PLCbeta, WDR36 augmented TPbeta receptor-induced [Ca(2+)]i increases. Surprisingly, WDR36 also augmented M3 receptor-induced [Ca(2+)]i increases, which was due to increased Ca(2+) mobilization while the Ca(2+) content of thapsigargin-sensitive stores remained unaltered. Interestingly, overexpression of WDR36 significantly delayed SphK1 translocation by Gq-coupled M3, B2 and H1 receptors in HEK-293 cells, while TPbeta receptor-induced SphK1 translocation was generally slow and not altered by WDR36 in these cells. Finally, in C2C12 myoblasts, overexpression of WDR36 delayed SphK1 translocation induced by B2 receptors. It is concluded that WDR36 reduces signalling of Gq-coupled receptors other than TPbeta towards PLC and SphK1, most likely by scavenging Galphaq and PLCbeta. Our results support a role of WDR36 in orchestration of Gq signalling complexes, and might help to functionally unravel its genetic association with asthma and allergy.
