Hayashi, YujiroAsuzu, David T.Gibbons, Simon J.Aarsvold, Kirsten H.Bardsley, Michael R.Lomberk, Gwen A.Mathison, Angela J.Kendrick, Michael L.Shen, K. RobertTaguchi, TakahiroGupta, AnuRubin, Brian P.Fletcher, JonathanFarrugia, GianricoUrrutia, Raul A.Ordog, Tamas2014-03-102013Hayashi, Y., D. T. Asuzu, S. J. Gibbons, K. H. Aarsvold, M. R. Bardsley, G. A. Lomberk, A. J. Mathison, et al. 2013. “Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways.” PLoS ONE 8 (10): e76822. doi:10.1371/journal.pone.0076822. http://dx.doi.org/10.1371/journal.pone.0076822.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:11878871Stem 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.en-USJournal Article2014-03-1010.1371/journal.pone.0076822