ArticleCancer letters2021
Mixed Lineage Kinase 3 phosphorylates prolyl-isomerase PIN1 and potentiates GLI1 signaling in pancreatic cancer development.
Article in Cancer letters, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 30 citations in OpenAlex.
- Hydrogen sulfide promotes proliferation and regeneration of human cerebral microvascular endothelial cells via the sonic hedgehog signaling pathway.Open life sciences · 2026Article
- Gedunin Impacts Pancreatic Cancer Stem Cells Through the Sonic Hedgehog Signaling Pathway.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC.Journal of medicinal chemistry · 2024Article
- CDK2-activated TRIM32 phosphorylation and nuclear translocation promotes radioresistance in triple-negative breast cancer.Journal of advanced research · 2024Article
- Article
- Phosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma.Nature communications · 2024Article
- The mechanisms of Pin1 as targets for cancer therapy.Frontiers in immunology · 2024Review
- The role of the master cancer regulator Pin1 in the development and treatment of cancer.Frontiers in cell and developmental biology · 2024Review
- Hedgehog-Gli1-derived exosomal circ-0011536 mediates peripheral neural remodeling in pancreatic cancer by modulating the miR-451a/VGF axis.Journal of experimental & clinical cancer research : CR · 2023Article
- MLK3 Regulates Inflammatory Response via Activation of AP-1 Pathway in HEK293 and RAW264.7 Cells.International journal of molecular sciences · 2022Article
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
The transcription factor Glioma-Associated Oncogene Homolog 1 (GLI1) is activated by sonic hedgehog (SHH) cascade and is an established driver of pancreatic ductal adenocarcinoma (PDAC). However, therapies targeting upstream hedgehog signaling have shown little to no efficacy in clinical trials. Here, we identify Mixed Lineage Kinase 3 (MLK3) as a druggable regulator of oncogenic GLI1. Earlier, we reported that MLK3 phosphorylated a peptidyl-prolyl isomerase PIN1 on the S138 site, and the PIN1-pS138 translocated to the nucleus. In this report, we identify GLI1 as one of the targets of PIN1-pS138 and demonstrate that PIN1-pS138 is upregulated in human PDAC and strongly associates with the upregulation of GLI1 and MLK3 expression. Moreover, we also identified two new phosphorylation sites on GLI1, T394, and S1089, which are directly phosphorylated by MLK3 to promote GLI1 nuclear translocation, transcriptional activity, and cell proliferation. Additionally, pharmacological inhibition of MLK3 by CEP-1347 promoted apoptosis in PDAC cell lines, reduced tumor burden, extended survival, and reduced GLI1 expression in the Pdx1-Cre x LSL-KRAS
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