Topic
CAMK1D
About: CAMK1D is a research topic. Over the lifetime, 5 publications have been published within this topic receiving 84 citations. The topic is also known as: CKLiK & CaM-K1.
Papers
TL;DR: Results suggest that rs11257655 affects transcriptional activity through altered binding of a protein complex that includes FOXA1 and FOXA2, providing a potential molecular mechanism at this GWAS locus.
Abstract: Many of the type 2 diabetes loci identified through genome-wide association studies localize to non-protein-coding intronic and intergenic regions and likely contain variants that regulate gene transcription. The CDC123/CAMK1D type 2 diabetes association signal on chromosome 10 spans an intergenic region between CDC123 and CAMK1D and also overlaps the CDC123 3′UTR. To gain insight into the molecular mechanisms underlying the association signal, we used open chromatin, histone modifications and transcription factor ChIP-seq data sets from type 2 diabetes-relevant cell types to identify SNPs overlapping predicted regulatory regions. Two regions containing type 2 diabetes-associated variants were tested for enhancer activity using luciferase reporter assays. One SNP, rs11257655, displayed allelic differences in transcriptional enhancer activity in 832/13 and MIN6 insulinoma cells as well as in human HepG2 hepatocellular carcinoma cells. The rs11257655 risk allele T showed greater transcriptional activity than the non-risk allele C in all cell types tested. Using electromobility shift and supershift assays we demonstrated that the rs11257655 risk allele showed allele-specific binding to FOXA1 and FOXA2. We validated FOXA1 and FOXA2 enrichment at the rs11257655 risk allele using allele-specific ChIP in human islets. These results suggest that rs11257655 affects transcriptional activity through altered binding of a protein complex that includes FOXA1 and FOXA2, providing a potential molecular mechanism at this GWAS locus.
102 citations
TL;DR: A lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.
Abstract: Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.
17 citations
TL;DR: Variants of mCaMKIδ possess distinct properties in terms of kinase activities, autophosphorylation and phosphorylation by another kinase, suggesting that they play physiologically different roles in murine cells.
Abstract: Ca2+/calmodulin (CaM)-dependent protein kinase Iδ (CaMKIδ) is a Ser/Thr kinase that plays pivotal roles in Ca2+ signalling. CaMKIδ is activated by Ca2+/CaM-binding and phosphorylation at Thr180 by CaMK kinase (CaMKK). In this study, we characterized four splice variants of mouse CaMKIδ (mCaMKIδs: a, b, c and d) found by in silico analysis. Recombinant mCaMKIδs expressed in Escherichia coli were phosphorylated by CaMKK; however, only mCaMKIδ-a and c showed protein kinase activities towards myelin basic protein in vitro, with mCaMKIδ-b and mCaMKIδ-d being inactive. Although mCaMKIδ-a and mCaMKIδ-c underwent autophosphorylation in vitro, only mCaMKIδ-c underwent autophosphorylation in 293T cells. Site-directed mutagenesis showed that the autophosphorylation site is Ser349, which is found in the C-terminal region of only variants c and b (Ser324). Furthermore, phosphorylation of these sites (Ser324 and Ser349) in mCaMKIδ-b and c was more efficiently catalyzed by cAMP-dependent protein kinase in vitro and in cellulo as compared to the autophosphorylation of mCaMKIδ-c. Thus, variants of mCaMKIδ possess distinct properties in terms of kinase activities, autophosphorylation and phosphorylation by another kinase, suggesting that they play physiologically different roles in murine cells.
3 citations
TL;DR: The backbone 1H, 13C, 15N assignments of the 38 kDa human CaMK1D protein in its free state are reported, including both the canonical bi-lobed kinase fold as well as the autoinhibitory and calmodulin binding domains.
Abstract: The CaMK subfamily of Ser/Thr kinases are regulated by calmodulin interactions with their C-terminal regions. They are exemplified by Ca2+/calmodulin dependent protein kinase 1δ which is known as CaMK1D, CaMKIδ or CKLiK. CaMK1D mediates intracellular signalling downstream of Ca2+ influx and thereby exhibits amplifications of Ca2+signals and polymorphisms that have been implicated in breast cancer and diabetes. Here we report the backbone 1H, 13C, 15N assignments of the 38 kDa human CaMK1D protein in its free state, including both the canonical bi-lobed kinase fold as well as the autoinhibitory and calmodulin binding domains.
1 citations
20 Feb 2015
TL;DR: The rs10752271 polymorphism in the CAMK1D gene may represent a novel tool for individualized antihypertensive treatment and belongs to the regulatory pathway involved in aldosterone synthesis.
Abstract: Aim: to identify genetic variants involved in blood pressure response to Losartan, an angiotensin II receptor blocker, with a whole genome approach.
Methods: n=722 never treated patients from Italy (SOPHIA study) with Essential Hypertension (EH): Losartan 50 mg o.d. was prescribed for 4 weeks to 539 patients. A genome-wide association study and imputation were perfomed on 494 patients. After quality control 372 patients remained for analysis To confirm the specificity of our findings, we tested their association with deltaSBP at 4wks in 458 patients treated with HCTZ. The best markers were tested for replication in two independent cohorts of hypertensives from the GERA2 and GENRES studies. Results: 131 SNPs were associated with deltaSBP4 (P≤10 -5 ), 121 of them to diastolic BP response. A peak of association in the Calcium/Calmodulin-dependent protein Kinase I D gene (CAMK1D) was identified: rs10752271 showed an effect size of -5.5±0.94mmHg and a P=1.2x10 -8 ). No association was found in HCTZ samples. In GENRES the association was confirmed (P=0.04, effect size=-5.3±2.5mmHg). Conclusion: The rs10752271 polymorphism in the CAMK1D gene may represent a novel tool for individualized antihypertensive treatment. The Calcium/Calmodulin-dependent protein Kinase I, CAMKI, belongs to the regulatory pathway involved in aldosterone synthesis. Circulating aldosterone levels were directly associated with an increase in blood pressure and the development of hypertension (Framingham Offspring Study).
1 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 1 |
| 2020 | 2 |
| 2015 | 1 |
| 2014 | 1 |