Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways

• Published in: PloS one Vol. 8; no. 10; p. e76822
• Main Authors: Hayashi, Yujiro, Asuzu, David T, Gibbons, Simon J, Aarsvold, Kirsten H, Bardsley, Michael R, Lomberk, Gwen A, Mathison, Angela J, Kendrick, Michael L, Shen, K Robert, Taguchi, Takahiro, Gupta, Anu, Rubin, Brian P, Fletcher, Jonathan A, Farrugia, Gianrico, Urrutia, Raul A, Ordog, Tamas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07-10-2013; Public Library of Science (PLoS)
• Subjects: Acetylation; AKT protein; Aminophenols - pharmacology; Animals; Autocrine signalling; Biomedical engineering; Blotting, Western; Cancer; Cell cycle; Cell Line; Cell Line, Tumor; Cell Membrane - metabolism; Cell Nucleus - metabolism; Cell proliferation; Cells, Cultured; Chromatin; Engineering; Epigenetics; Gastroenterology; Gastrointestinal cancer; Gastrointestinal Stromal Tumors - genetics; Gastrointestinal Stromal Tumors - metabolism; Gastrointestinal Stromal Tumors - pathology; Gene expression; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Glycogen synthesis; Hepatic Stellate Cells - cytology; Hepatic Stellate Cells - metabolism; Hepatology; Histone H3; Histones - metabolism; Humans; Impact prediction; Inhibition; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factors; Interstitial cells; Interstitial cells of Cajal; Interstitial Cells of Cajal - cytology; Interstitial Cells of Cajal - metabolism; Kinases; Ligands; Lysine; Maleimides - pharmacology; Methylation; Methylation - drug effects; Methyltransferase; Mice; Mice, Inbred BALB C; Mice, Knockout; Muscles; Mutation; Neurosciences; Nuclei; Nuclei (cytology); Paracrine signalling; Pathology; Peptides; Pharmacology; Physiology; Precision medicine; Proteins; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA-mediated interference; Rodents; Sarcoma; Signal transduction; Signal Transduction - drug effects; Smooth muscle; Stem Cell Factor - genetics; Stem Cell Factor - metabolism; Stem cells; Transcription, Genetic - drug effects; Tumors; Cleveland Ohio; Minnesota; Ohio; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0076822

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.