Protein Kinase PKN1 Represses Wnt/β-Catenin Signaling in Human Melanoma Cells

James, Richard G.; Bosch, Katherine A.; Kulikauskas, Rima M.; Yang, Peter; Robin, Nick C.; Toroni, Rachel A.; Biechele, Travis L.; Berndt, Jason D.; Haller, Priska D. von; Eng, Jimmy K.; Wolf-Yadlin, Alejandro; Chien, Andy J.; Moon, Randall T.

doi:10.1074/jbc.m113.500314

Cited by 30 publications

(29 citation statements)

References 64 publications

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“…In OA, hypermethylated PKN1 may be responsible for NF-κB activation after self-expression inhibition, or it may be the result of long-term stimulation of chronic in ammation, which requires further research to explain. At the same time, PKN1 inhibits Wnt/β-catenin signalling in a human melanoma cell research (38), suggesting that the role of PKN1 in the pathogenesis of OA should not be underestimated.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide DNA Methylation Profile Reveals Potential Therapeutic Targets at the Late Stage of Knee Osteoarthritis

Shen¹,

Long²,

Zhang³

et al. 2020

Preprint

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Background: The aim of this study was to use the latest BeadChip technology to obtain a genome-wide DNA methylation profile for cartilage from patients with primary knee osteoarthritis (OA), providing the first comprehensive description of DNA methylation changes in advanced knee OA. Methods: Cartilage tissues were taken from patients after total knee arthroplasty and were divided into eroded group and intact group according to the cartilage status. The genome-wide DNA methylation profile was obtained using the Infinium MethylationEPIC BeadChip kit, which enables the analysis of >850,000 CpG sites. Comparisons of the two groups were performed to identify differentially methylated (DM) probes (DMPs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied to the functional annotation clustering of the DM genes. Results: There was significant differential methylation between the two groups, and a total of 16,776 DMPs covering approximately 6,700 genes were identified, 92% of which were hypomethylated. Functional enrichment results revealed that the DM genes were significantly enriched for the extracellular matrix (ECM) proteins, cell adhesion molecules (CAM) and proteins in some inflammatory response pathways, especially the PI3K/Akt signalling pathway. Six genes including RNF43, SEMA4D, F11R, PKN1, FLT-1 and PTPN11 may be the potential biomarkers for OA.Conclusion: Our data demonstrate the epigenetic dysregulation of many genes and pathways in the late stage of knee OA that appear to be involved in potential aetiological mechanisms of OA. DM genes closely associated with OA may become targets for treatment and may open new avenues for further research in the field.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide DNA Methylation Profile Reveals Potential Therapeutic Targets at the Late Stage of Knee Osteoarthritis

Shen¹,

Long²,

Zhang³

et al. 2020

Preprint

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“…Each lysate mix was then independently reduced, alkylated, trypsinized and desalted [24]. Phosphopeptide enrichment was performed as detailed previously [25]. …”

Section: Methodsmentioning

confidence: 99%

The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans

Dam¹,

Habib²,

Chen³

et al. 2016

Clinical Immunology

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the development of autoantibodies that drive disease pathogenesis. Genetic studies have associated nonsynonymous variants in the BANK1 B cell scaffolding gene with susceptibility to SLE and autoantibodies in lupus. To determine how the BANK1 SLE-risk variants contribute to the dysregulated B cell program in lupus, we performed genotype/phenotype studies in human B cells. Targeted phospho-proteomics were used to evaluate BCR/CD40 signaling in human B cell lines engineered to express the BANK1 risk or non-risk variant proteins. We found that phosphorylation of proximal BCR signaling molecules was reduced in B cells expressing the BANK1 risk protein compared to the non-risk protein. Similar to these findings, we observed decreased B cell signaling in primary B cells from genotyped healthy control subjects carrying the BANK1 risk haplotype, including blunted BCR- and CD40-dependent AKT activation. Consistent with decreased AKT activation, we found that BANK1 risk B cells expressed increased basal levels of FOXO1 protein and increased expression of FOXO1 target genes upon stimulation compared to non-risk B cells. Healthy subjects carrying the BANK1 risk haplotype were also characterized by an expansion of memory B cells. Taken together, our results suggest that the SLE susceptibility variants in the BANK1 gene may contribute to lupus by altering B cell signaling, increasing FOXO1 levels, and enhancing memory B cell development.

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“…The top scoring gene in the module, PKN1 (protein-kinase-C-related kinase), controls processes such as regulation of the intermediate filaments of the actin cytoskeleton, tumor cell invasion, and cell migration 57 . It is activated by the Rho family of small G-proteins and might mediate the Rho-dependent signaling pathway 58 , which was one of the main enriched pathways in the module-level analysis. PKN1 has also been described as an important player in other cancers: in androgen-associated prostate cancer by controlling migration and metastasis 57 or in melanomas by inhibiting Wnt/ β-catenin signaling and apoptosis 58 .…”

Section: Single Variant and Gene Analyses Detect One Independent Hitmentioning

confidence: 99%

“…It is activated by the Rho family of small G-proteins and might mediate the Rho-dependent signaling pathway 58 , which was one of the main enriched pathways in the module-level analysis. PKN1 has also been described as an important player in other cancers: in androgen-associated prostate cancer by controlling migration and metastasis 57 or in melanomas by inhibiting Wnt/ β-catenin signaling and apoptosis 58 .…”

Section: Single Variant and Gene Analyses Detect One Independent Hitmentioning

confidence: 99%

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

et al. 2020

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Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)negative and one in ER-positive disease. The modules show biological enrichment for cancerrelated processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.

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Protein Kinase PKN1 Represses Wnt/β-Catenin Signaling in Human Melanoma Cells

Cited by 30 publications

References 64 publications

Genome-Wide DNA Methylation Profile Reveals Potential Therapeutic Targets at the Late Stage of Knee Osteoarthritis

Genome-Wide DNA Methylation Profile Reveals Potential Therapeutic Targets at the Late Stage of Knee Osteoarthritis

The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

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