ArticleCell death and differentiation2014
Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation.
Article in Cell death and differentiation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 93 citations in OpenAlex.
- Clinical Applications of Assisted Oocyte Activation in Couples with Various Reproductive Problems: A Systematic Review.Reproductive sciences (Thousand Oaks, Calif.) · 2024Pooled it
- Reduced type 2 epithelial-mesenchymal transition serves as a risk factor for the progression from endometriosis to endometriosis-associated ovarian cancer.Scientific reports · 2026Article
- Intertwining of the IGF system and animal welfare.Scientific reports · 2026Article
- A novel small molecule NJH-13 induces pyroptosis via the CaJournal of advanced research · 2025Article
- Effects of Different Salinity Conditions on Regulation ofInternational journal of molecular sciences · 2025Article
- PRMT3-Mediated H4R3me2a Promotes Primary Age-Related Tauopathy by Driving Tau Hyperphosphorylation in Neuron.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Transient Receptor Potential Channels in Prostate Cancer: Associations with ERG Fusions and Survival.International journal of molecular sciences · 2025Article
- Delta opioid peptide [D-ala2, D-leu5]-Enkephalin's ability to enhance mitophagy via TRPV4 to relieve ischemia/reperfusion injury in brain microvascular endothelial cells.Stroke and vascular neurology · 2025Article
- Sox10 is required for systemic initiation of bone mineralization.Development (Cambridge, England) · 2025Article
- Stc2a inhibits IGF-stimulated somatic growth in favor of organismal survival under hypoxic stress.Frontiers in endocrinology · 2025Article
- Spatio-Temporal Regulation of IGFs in Enamel Development: Molecular Mechanisms From Ameloblast Polarity to Mineralization Homeostasis.Stem cells international · 2025Review
- Environmental and molecular control of tissue-specific ionocyte differentiation in zebrafish.Development (Cambridge, England) · 2024Article
- Review
- Neurophysiology, Neuro-Immune Interactions, and Mechanobiology in Osteopathy in the Cranial Field: An Evidence-Informed Perspective for a Scientific Rationale.Healthcare (Basel, Switzerland) · 2023Article
- Calcium signals and potential therapy targets in ovarian cancer (Review).International journal of oncology · 2023Review
- TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches.Biomolecules · 2023Review
- Insulin signaling in development.Development (Cambridge, England) · 2023Article
- ROS signaling-induced mitochondrial Sgk1 expression regulates epithelial cell renewal.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Novel discovery of schisandrin A regulating the interplay of autophagy and apoptosis in oligoasthenospermia by targeting SCF/c-kit and TRPV1Acta pharmaceutica Sinica. B · 2023Article
- Pan-Cancer Analysis of the TRP Family, Especially TRPV4 and TRPC4, and Its Expression Correlated with Prognosis, Tumor Microenvironment, and Treatment Sensitivity.Biomolecules · 2023Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Calcium deficiency causes abnormal colonic growth and increases colon cancer risk with poorly understood mechanisms. Here we elucidate a novel signaling mechanism underlying the Ca(2+) deficiency-induced epithelial proliferation using a unique animal model. The zebrafish larval yolk sac skin contains a group of Ca(2+)-transporting epithelial cells known as ionocytes. Their number and density increases dramatically when acclimated to low [Ca(2+)] environments. BrdU pulse-labeling experiments suggest that low [Ca(2+)] stimulates pre-existing ionocytes to re-enter the cell cycle. Low [Ca(2+)] treatment results in a robust and sustained activation of IGF1R-PI3K-Akt signaling in these cells exclusively. These ionocytes specifically express Igfbp5a, a high-affinity and specific binding protein for insulin-like growth factors (IGFs) and the Ca(2+)-selective channel Trpv5/6. Inhibition or knockdown of Igfbp5a, IGF1 receptor, PI3K, and Akt attenuates low [Ca(2+)]-induced ionocyte proliferation. The role of Trpv5/6 was investigated using a genetic mutant, targeted knockdown, and pharmacological inhibition. Loss-of-Trpv5/6 function or expression results in elevated pAkt levels and increased ionocyte proliferation under normal [Ca(2+)]. These increases are eliminated in the presence of an IGF1R inhibitor, suggesting that Trpv5/6 represses IGF1R-PI3K-Akt signaling under normal [Ca(2+)]. Intriguingly, blockade of Trpv5/6 activity inhibits the low [Ca(2+)]-induced activation of Akt. Mechanistic analyses reveal that the low [Ca(2+)]-induced IGF signaling is mediated through Trpv5/6-associated membrane depolarization. Low extracellular [Ca(2+)] results in a similar amplification of IGF-induced PI3K-PDK1-Akt signaling in human colon cancer cells in a TRPV6-dependent manner. These results uncover a novel and evolutionarily conserved signaling mechanism that contributes to the abnormal epithelial proliferation associated with Ca(2+) deficiency.
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