title: Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways.
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.
authors.affiliation: Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America ; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: David T
authors.initials: DT
authors.lastname: Asuzu
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Gibbons
authors.forename: Kirsten H
authors.initials: KH
authors.lastname: Aarsvold
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bardsley
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Lomberk
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Mathison
authors.forename: Michael L
authors.initials: ML
authors.lastname: Kendrick
authors.forename: K Robert
authors.initials: KR
authors.lastname: Shen
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.forename: Anu
authors.initials: A
authors.lastname: Gupta
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
authors.forename: Raul A
authors.initials: RA
authors.lastname: Urrutia
authors.forename: Tamas
authors.initials: T
authors.lastname: Ordog
mesh_terms: D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D056885:Interstitial Cells of Cajal / Q000166:cytology / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D006657:Histones; D008301:Maleimides; D019089:Stem Cell Factor; D007334:Insulin-Like Growth Factor I; D019009:Proto-Oncogene Proteins c-kit; D017526:Receptor, IGF Type 1; D038362:Glycogen Synthase Kinase 3