ArticleThe Journal of biological chemistry2018
TGFβ and IGF1R signaling activates protein kinase A through differential regulation of ezrin phosphorylation in colon cancer cells.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 22 citations in OpenAlex.
- Review
- A functional variant rs10409772 in FUT6 promoter regulates colorectal cancer progression through PKA/CREB signaling.Translational oncology · 2024Article
- PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment.International journal of molecular sciences · 2024Review
- Role of Ezrin in Asthma-Related Airway Inflammation and Remodeling.Mediators of inflammation · 2022Review
- The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression.International journal of molecular sciences · 2021Article
- Colon Cancer-Related Genes Identification and Function Study Based on Single-Cell Multi-Omics Integration.Frontiers in cell and developmental biology · 2021Article
- Correlation of PRL3 expression with colorectal cancer progression.Journal of surgical oncology · 2021Article
- Complex roles of cAMP-PKA-CREB signaling in cancer.Experimental hematology & oncology · 2020Review
- GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing.Stem cells translational medicine · 2020Article
- Emerging Importance of Survivin in Stem Cells and Cancer: the Development of New Cancer Therapeutics.Stem cell reviews and reports · 2020Review
- Prognostic and therapeutic implications of NHERF1 expression and regulation in colorectal cancer.Journal of surgical oncology · 2020Article
- Identification of differentially expressed genes regulated by methylation in colon cancer based on bioinformatics analysis.World journal of gastroenterology · 2019Article
- High blood sugar levels but not diabetes mellitus significantly enhance oxaliplatin chemoresistance in patients with stage III colorectal cancer receiving adjuvant FOLFOX6 chemotherapy.Therapeutic advances in medical oncology · 2019Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Aberrant cell survival plays a critical role in cancer progression and metastasis. We have previously shown that ezrin, a cAMP-dependent protein kinase A-anchoring protein (AKAP), is up-regulated in colorectal cancer (CRC) liver metastasis. Phosphorylation of ezrin at Thr-567 activates ezrin and plays an important role in CRC cell survival associated with XIAP and survivin up-regulation. In this study, we demonstrate that in FET and GEO colon cancer cells, knockdown of ezrin expression or inhibition of ezrin phosphorylation at Thr-567 increases apoptosis through protein kinase A (PKA) activation in a cAMP-independent manner. Transforming growth factor (TGF) β signaling inhibits ezrin phosphorylation in a Smad3-dependent and Smad2-independent manner and regulates pro-apoptotic function through ezrin-mediated PKA activation. On the other hand, ezrin phosphorylation at Thr-567 by insulin-like growth factor 1 receptor (IGF1R) signaling leads to cAMP-dependent PKA activation and enhances cell survival. Further studies indicate that phosphorylated ezrin forms a complex with PKA RII, and dephosphorylated ezrin dissociates from the complex and facilitates the association of PKA RII with AKAP149, both of which activate PKA yet lead to either cell survival or apoptosis. Thus, our studies reveal a novel mechanism of differential PKA activation mediated by TGFβ and IGF1R signaling through regulation of ezrin phosphorylation in CRC, resulting in different cell fates. This is of significance because TGFβ and IGF1R signaling pathways are well-characterized tumor suppressor and oncogenic pathways, respectively, with important roles in CRC tumorigenesis and metastasis. Our studies indicate that they cross-talk and antagonize each other's function through regulation of ezrin activation. Therefore, ezrin may be a potential therapeutic target in CRC.
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