ArticlePloS one2013
Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Linsitinib (OSI-906) for the Treatment of Adult and Pediatric Wild-Type Gastrointestinal Stromal Tumors, a SARC Phase II Study.Clinical cancer research : an official journal of the American Association for Cancer Research · 2020Trial
- New variant in KITLG shapes the pathogenesis of familial progressive hyper- and hypo-pigmentation.Molecular genetics and genomics : MGG · 2026Article
- Prediction of Skin Color Using Forensic DNA Phenotyping in Asian Populations: A Focus on Thailand.Biomolecules · 2025Review
- Cellular and molecular mechanisms underlying aging-related gastric neuromuscular dysfunction.Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi · 2025Review
- Improving Gastric Motility in Aging Through EZH2 Inhibition and Preservation of Interstitial Cells of Cajal.Cellular and molecular gastroenterology and hepatology · 2024Article
- Protocol for gene knockdown using siRNA in organotypic cultures of murine gastric muscle.Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi · 2024Article
- Review
- Article
- Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During Aging.Cellular and molecular gastroenterology and hepatology · 2021Article
- Function of insulin-like growth factor 1 receptor in cancer resistance to chemotherapy.Oncology letters · 2018Article
- Hyperglycemia Increases Interstitial Cells of Cajal via MAPK1 and MAPK3 Signaling to ETV1 and KIT, Leading to Rapid Gastric Emptying.Gastroenterology · 2017Article
- Commentary: Phase-amplitude coupling at the organism level: The amplitude of spontaneous alpha rhythm fluctuations varies with the phase of the infra-slow gastric basal rhythm.Frontiers in neuroscience · 2017Article
- Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression.Oncotarget · 2016Article
- Altered gut microbiota in female mice with persistent low body weights following removal of post-weaning chronic dietary restriction.Genome medicine · 2016Article
- Platelet-Derived Growth Factor Receptor-α Regulates Proliferation of Gastrointestinal Stromal Tumor Cells With Mutations in KIT by Stabilizing ETV1.Gastroenterology · 2015Article
- Targeting Disease Persistence in Gastrointestinal Stromal Tumors.Stem cells translational medicine · 2015Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
Abstract
Stem cell factor (mouse: Kitl, human: KITLG) and insulin-like growth factor-1 (IGF1), acting via KIT and IGF1 receptor (IGF1R), respectively, are critical for the development and integrity of several tissues. Autocrine/paracrine KITLG-KIT and IGF1-IGF1R signaling are also activated in several cancers including gastrointestinal stromal tumors (GIST), the most common sarcoma. In murine gastric muscles, IGF1 promotes Kitl-dependent development of interstitial cells of Cajal (ICC), the non-neoplastic counterpart of GIST, suggesting cooperation between these pathways. Here, we report a novel mechanism linking IGF1-IGF1R and KITLG-KIT signaling in both normal and neoplastic cells. In murine gastric muscles, the microenvironment for ICC and GIST, human hepatic stellate cells (LX-2), a model for cancer niches, and GIST cells, IGF1 stimulated Kitl/KITLG protein and mRNA expression and promoter activity by activating several signaling pathways including AKT-mediated glycogen synthase kinase-3β inhibition (GSK3i). GSK3i alone also stimulated Kitl/KITLG expression without activating mitogenic pathways. Both IGF1 and GSK3i induced chromatin-level changes favoring transcriptional activation at the Kitl promoter including increased histone H3/H4 acetylation and H3 lysine (K) 4 methylation, reduced H3K9 and H3K27 methylation and reduced occupancy by the H3K27 methyltransferase EZH2. By pharmacological or RNA interference-mediated inhibition of chromatin modifiers we demonstrated that these changes have the predicted impact on KITLG expression. KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine/paracrine KITLG-KIT signaling. We conclude that membrane-to-nucleus signaling involving GSK3i establishes a previously unrecognized link between the IGF1-IGF1R and KITLG-KIT pathways, which is active in both physiologic and oncogenic contexts and can be exploited for therapeutic purposes.
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