ArticleCell death and differentiation2022
The Smad4-MYO18A-PP1A complex regulates β-catenin phosphorylation and pemigatinib resistance by inhibiting PAK1 in cholangiocarcinoma.
Article in Cell death and differentiation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 41 citations in OpenAlex.
- Druggable β-catenin palmitoyl-switch coordinates immune evasion via immunogenic ferroptosis resistance and PD-L1-mediated immunosuppression.Cell reports. Medicine · 2026Article
- Comprehensive Genomic Profiles of Patients With Biliary Tract Cancer.Cancer medicine · 2026Article
- EEF1AKMT4-eEF1A2 synergistically facilitates the progression of GBC by promoting ribosomal protein output.Genes & diseases · 2026Article
- PTTG1-DLX2 axis drives malignant progression of lung adenocarcinoma by activating the WNT/β-catenin signaling pathway.Translational cancer research · 2026Article
- Integrative phosphoproteomic analysis reveals co-regulatory phosphorylation networks of rhotekin in cancer progression.Discover oncology · 2026Article
- MYO18A Expression is a Prognostic Factor for Progression-Free Survival in Grade 4 Adult gliomas. Preliminary Report.Oncology research · 2026Article
- The diagnostic and therapeutic potential of miR-3149 in osteoporotic fractures through SMAD4.Journal of orthopaedic surgery and research · 2025Article
- Targeting the ROCK2/UBA52/DRP1 axis enhances ferroptosis and overcomes pemigatinib resistance in Cholangiocarcinoma.Cell death & disease · 2025Article
- PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- AMDHD1 acts as a tumor suppressor and contributes to activation of TGF-β signaling pathway in cholangiocarcinoma.Cell death and differentiation · 2025Article
- Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia.Leukemia · 2025Article
- Function of histamine-driven cancer-associated fibroblast and hepatocyte growth factor in the progression of cholangiocarcinoma.Gastroenterology report · 2025Article
- Protein serine/threonine phosphatases in tumor microenvironment: a vital player and a promising therapeutic target.Theranostics · 2025Review
- The Epstein-Barr virus-miRNA-BART6-5p regulates TGF-β/SMAD4 pathway to induce glycolysis and enhance proliferation and metastasis of gastric cancer cells.Oncology research · 2024Article
- Integrin β5 is an independent prognostic marker for intrahepatic cholangiocarcinoma in a Chinese population.Experimental and therapeutic medicine · 2023Article
- SMAD4 regulates the progression of cholangiocarcinoma by modulating the expression of STING1.Journal of cellular and molecular medicine · 2023Article
- Development and validation of a gene expression-based nomogram to predict the prognosis of patients with cholangiocarcinoma.Journal of cancer research and clinical oncology · 2023Article
- SMAD Proteins in TGF-β Signalling Pathway in Cancer: Regulatory Mechanisms and Clinical Applications.Diagnostics (Basel, Switzerland) · 2023Review
- ATRA sensitized the response of hepatocellular carcinoma to Sorafenib by downregulation of p21-activated kinase 1.Cell communication and signaling : CCS · 2023Article
- Programmed Cell Death Pathways in Cholangiocarcinoma: Opportunities for Targeted Therapy.Cancers · 2023Review
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cholangiocarcinoma (CCA), consisting of three subtypes-intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA), is a highly aggressive cancer arising from the bile duct and has an extremely poor prognosis. Pemigatinib is the only FDA-approved targeted drug for CCA, and the CCA treatment options are substantially insufficient considering its poor prognosis and increasing morbidity. Here, we performed next-generation sequencing (NGS) of 15 pCCAs and 16 dCCAs and detected the expression of SMAD4, a frequently mutated gene, in 261 CCAs. By univariate and multivariate analyses, we identified Smad4 as a favorable prognostic biomarker in iCCA and pCCA. With in vitro and in vivo experiments, we demonstrated that Smad4 suppressed CCA proliferation, migration and invasion by inhibiting β-catenin-S675 phosphorylation and intranuclear translocation. We applied LC-MS/MS and multiple biochemical techniques and identified PP1A as the phosphatase in Smad4-mediated dephosphorylation of PAK1-T423, which is responsible for β-catenin-S675 phosphorylation. Moreover, we demonstrated that MYO18A is the PP1-interacting protein of PP1A for substrate recognition in CCA. MYO18A interacts with PP1A via its RVFFR motif and interacts with Smad4 via CC domain. Patients with coexpression of MYO18A and Smad4 have a more favorable prognosis than other patients. Smad4 enhances Pemigatinib efficiency, and Smad4 knockdown results in Pemigatinib resistance. In conclusion, coexpression of Smad4 and MYO18A is a favorable prognostic indicator for iCCA and pCCA. The Smad4-MYO18A-PP1A complex dephosphorylates PAK1-T423 and thus inhibits β-catenin-S675 phosphorylation and its intranuclear localization. Smad4 suppresses CCA proliferation, migration, invasion, and sensitivity to Pemigatinib by governing the phosphorylation and intracellular localization of β-catenin.
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