Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways

Yujiro Hayashi, David T. Asuzu, Simon J. Gibbons, Kirsten H. Aarsvold, Michael R. Bardsley, Gwen A. Lomberk, Angela J. Mathison, Michael L. Kendrick, K. Robert Shen, Takahiro Taguchi, Anu Gupta, Brian P. Rubin, Jonathan A. Fletcher, Gianrico Farrugia, Raul A. Urrutia, Tamas Ordog

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere76822
JournalPLoS One
Volume8
Issue number10
DOIs
StatePublished - Oct 7 2013

Fingerprint

stem cell factor
Stem Cell Factor
somatomedins
Somatomedins
Gastrointestinal Stromal Tumors
Glycogen Synthase Kinase 3
Membranes
neoplasms
stromal cells
Tumors
methylation
chromatin
mice
stomach
Interstitial Cells of Cajal
promoter regions
muscles
Methylation
modifiers (genes)
Stromal Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Hayashi, Y., Asuzu, D. T., Gibbons, S. J., Aarsvold, K. H., Bardsley, M. R., Lomberk, G. A., ... Ordog, T. (2013). Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways. PLoS One, 8(10), [e76822]. https://doi.org/10.1371/journal.pone.0076822

Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways. / 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.

In: PLoS One, Vol. 8, No. 10, e76822, 07.10.2013.

Research output: Contribution to journalArticle

Hayashi, Y, Asuzu, DT, Gibbons, SJ, Aarsvold, KH, Bardsley, MR, Lomberk, GA, Mathison, AJ, Kendrick, ML, Shen, KR, Taguchi, T, Gupta, A, Rubin, BP, Fletcher, JA, Farrugia, G, Urrutia, RA & Ordog, T 2013, 'Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways', PLoS One, vol. 8, no. 10, e76822. https://doi.org/10.1371/journal.pone.0076822
Hayashi Y, Asuzu DT, Gibbons SJ, Aarsvold KH, Bardsley MR, Lomberk GA et al. Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways. PLoS One. 2013 Oct 7;8(10). e76822. https://doi.org/10.1371/journal.pone.0076822
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. / Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways. In: PLoS One. 2013 ; Vol. 8, No. 10.
@article{0f1b1451274a4d56a5ac91898ed85af8,
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.",
author = "Yujiro Hayashi and Asuzu, {David T.} and Gibbons, {Simon J.} and Aarsvold, {Kirsten H.} and Bardsley, {Michael R.} and Lomberk, {Gwen A.} and Mathison, {Angela J.} and Kendrick, {Michael L.} and Shen, {K. Robert} and Takahiro Taguchi and Anu Gupta and Rubin, {Brian P.} and Fletcher, {Jonathan A.} and Gianrico Farrugia and Urrutia, {Raul A.} and Tamas Ordog",
year = "2013",
month = "10",
day = "7",
doi = "10.1371/journal.pone.0076822",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways

AU - Hayashi, Yujiro

AU - Asuzu, David T.

AU - Gibbons, Simon J.

AU - Aarsvold, Kirsten H.

AU - Bardsley, Michael R.

AU - Lomberk, Gwen A.

AU - Mathison, Angela J.

AU - Kendrick, Michael L.

AU - Shen, K. Robert

AU - Taguchi, Takahiro

AU - Gupta, Anu

AU - Rubin, Brian P.

AU - Fletcher, Jonathan A.

AU - Farrugia, Gianrico

AU - Urrutia, Raul A.

AU - Ordog, Tamas

PY - 2013/10/7

Y1 - 2013/10/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84885041041&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885041041&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0076822

DO - 10.1371/journal.pone.0076822

M3 - Article

C2 - 24116170

AN - SCOPUS:84885041041

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e76822

ER -