LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1 -Rac1 pathway

Kendra S. Carmon, Gong Xing, Jing Yi, Ling Wu, Anthony Thomas, Catherine Moore, Ikuo Masuho, David Timson, Kirill A. Martemyanov, Qingyun J. Liu

Research output: Contribution to journalArticle

Abstract

Leucine rich repeat containing G protein coupled receptor 5 (LGR5) is a bona fide marker of adult stem cells in several epithelial tissues, most notably in the intestinal crypts and is highly upregulated in many colorectal, hepatocellular, and ovarian cancers. LGR5 activation by R-spondin (RSPO) ligands potentiates Wnt/β-catenin signaling in vitro, yet deletion of LGR5 in stem cells has little or no effect on Wnt/β-catenin signaling or cell proliferation in vivo. Remarkably, modulation of LGR5 expression has a major impact on the actin cytoskeletal structure and cell adhesion in the absence of RSPO stimulation, but the molecular mechanism is unclear. Here, we show that LGR5 interacts with IQ motif containing GTPase activating protein 1 (IQGAP1), an effector of Rac1/CDC42 GTPases, in the regulation of actin cytoskeleton dynamics and cell-cell adhesion. Specifically, LGR5 decreased levels of IQGAP1 phosphorylation at Ser-1441/1443, leading to increased binding of Rac1 to IQGAP1 and thus higher levels of cortical F-actin and enhanced cell-cell adhesion. LGR5 ablation in colon cancer cells and crypt stem cells resulted in loss of cortical F-actin, reduced cell-cell adhesion, and disrupted localization of adhesion-associated proteins. No evidence of LGR5 coupling to any of the four major subtypes of heterotrimeric G proteins was found. These findings suggest that LGR5 primarily functions via the IQGAP1-Rac1 pathway to strengthen cell-cell adhesion in normal adult crypt stem cells and colon cancer cells.
Original languageEnglish
Pages (from-to)14989-15001
Number of pages13
JournalJournal of Biological Chemistry
Volume292
DOIs
Publication statusPublished - 24 Jul 2017

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Cell Adhesion
Colonic Neoplasms
Stem Cells
Actins
Catenins
Adult Stem Cells
Heterotrimeric GTP-Binding Proteins
GTP Phosphohydrolases
Liver Neoplasms
G-Protein-Coupled Receptors
Actin Cytoskeleton
Leucine
Ovarian Neoplasms
IQ motif containing GTPase activating protein 1
Colorectal Neoplasms
Epithelium
Phosphorylation
Cell Proliferation
Ligands
Proteins

Bibliographical note

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Author's Choice—Final version free via Creative Commons CC-BY license.

Keywords

  • 7-helix receptor
  • adhesion
  • cancer stem cells
  • G protein-coupled receptor (GPCR)
  • intestine

Cite this

Carmon, Kendra S. ; Xing, Gong ; Yi, Jing ; Wu, Ling ; Thomas, Anthony ; Moore, Catherine ; Masuho, Ikuo ; Timson, David ; Martemyanov, Kirill A. ; Liu, Qingyun J. / LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1 -Rac1 pathway. In: Journal of Biological Chemistry. 2017 ; Vol. 292. pp. 14989-15001.
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abstract = "Leucine rich repeat containing G protein coupled receptor 5 (LGR5) is a bona fide marker of adult stem cells in several epithelial tissues, most notably in the intestinal crypts and is highly upregulated in many colorectal, hepatocellular, and ovarian cancers. LGR5 activation by R-spondin (RSPO) ligands potentiates Wnt/β-catenin signaling in vitro, yet deletion of LGR5 in stem cells has little or no effect on Wnt/β-catenin signaling or cell proliferation in vivo. Remarkably, modulation of LGR5 expression has a major impact on the actin cytoskeletal structure and cell adhesion in the absence of RSPO stimulation, but the molecular mechanism is unclear. Here, we show that LGR5 interacts with IQ motif containing GTPase activating protein 1 (IQGAP1), an effector of Rac1/CDC42 GTPases, in the regulation of actin cytoskeleton dynamics and cell-cell adhesion. Specifically, LGR5 decreased levels of IQGAP1 phosphorylation at Ser-1441/1443, leading to increased binding of Rac1 to IQGAP1 and thus higher levels of cortical F-actin and enhanced cell-cell adhesion. LGR5 ablation in colon cancer cells and crypt stem cells resulted in loss of cortical F-actin, reduced cell-cell adhesion, and disrupted localization of adhesion-associated proteins. No evidence of LGR5 coupling to any of the four major subtypes of heterotrimeric G proteins was found. These findings suggest that LGR5 primarily functions via the IQGAP1-Rac1 pathway to strengthen cell-cell adhesion in normal adult crypt stem cells and colon cancer cells.",
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Carmon, KS, Xing, G, Yi, J, Wu, L, Thomas, A, Moore, C, Masuho, I, Timson, D, Martemyanov, KA & Liu, QJ 2017, 'LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1 -Rac1 pathway', Journal of Biological Chemistry, vol. 292, pp. 14989-15001. https://doi.org/10.1074/jbc.M117.786798

LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1 -Rac1 pathway. / Carmon, Kendra S.; Xing, Gong; Yi, Jing; Wu, Ling; Thomas, Anthony; Moore, Catherine; Masuho, Ikuo; Timson, David; Martemyanov, Kirill A.; Liu, Qingyun J.

In: Journal of Biological Chemistry, Vol. 292, 24.07.2017, p. 14989-15001.

Research output: Contribution to journalArticle

TY - JOUR

T1 - LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1 -Rac1 pathway

AU - Carmon, Kendra S.

AU - Xing, Gong

AU - Yi, Jing

AU - Wu, Ling

AU - Thomas, Anthony

AU - Moore, Catherine

AU - Masuho, Ikuo

AU - Timson, David

AU - Martemyanov, Kirill A.

AU - Liu, Qingyun J.

N1 - © 2017 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license.

PY - 2017/7/24

Y1 - 2017/7/24

N2 - Leucine rich repeat containing G protein coupled receptor 5 (LGR5) is a bona fide marker of adult stem cells in several epithelial tissues, most notably in the intestinal crypts and is highly upregulated in many colorectal, hepatocellular, and ovarian cancers. LGR5 activation by R-spondin (RSPO) ligands potentiates Wnt/β-catenin signaling in vitro, yet deletion of LGR5 in stem cells has little or no effect on Wnt/β-catenin signaling or cell proliferation in vivo. Remarkably, modulation of LGR5 expression has a major impact on the actin cytoskeletal structure and cell adhesion in the absence of RSPO stimulation, but the molecular mechanism is unclear. Here, we show that LGR5 interacts with IQ motif containing GTPase activating protein 1 (IQGAP1), an effector of Rac1/CDC42 GTPases, in the regulation of actin cytoskeleton dynamics and cell-cell adhesion. Specifically, LGR5 decreased levels of IQGAP1 phosphorylation at Ser-1441/1443, leading to increased binding of Rac1 to IQGAP1 and thus higher levels of cortical F-actin and enhanced cell-cell adhesion. LGR5 ablation in colon cancer cells and crypt stem cells resulted in loss of cortical F-actin, reduced cell-cell adhesion, and disrupted localization of adhesion-associated proteins. No evidence of LGR5 coupling to any of the four major subtypes of heterotrimeric G proteins was found. These findings suggest that LGR5 primarily functions via the IQGAP1-Rac1 pathway to strengthen cell-cell adhesion in normal adult crypt stem cells and colon cancer cells.

AB - Leucine rich repeat containing G protein coupled receptor 5 (LGR5) is a bona fide marker of adult stem cells in several epithelial tissues, most notably in the intestinal crypts and is highly upregulated in many colorectal, hepatocellular, and ovarian cancers. LGR5 activation by R-spondin (RSPO) ligands potentiates Wnt/β-catenin signaling in vitro, yet deletion of LGR5 in stem cells has little or no effect on Wnt/β-catenin signaling or cell proliferation in vivo. Remarkably, modulation of LGR5 expression has a major impact on the actin cytoskeletal structure and cell adhesion in the absence of RSPO stimulation, but the molecular mechanism is unclear. Here, we show that LGR5 interacts with IQ motif containing GTPase activating protein 1 (IQGAP1), an effector of Rac1/CDC42 GTPases, in the regulation of actin cytoskeleton dynamics and cell-cell adhesion. Specifically, LGR5 decreased levels of IQGAP1 phosphorylation at Ser-1441/1443, leading to increased binding of Rac1 to IQGAP1 and thus higher levels of cortical F-actin and enhanced cell-cell adhesion. LGR5 ablation in colon cancer cells and crypt stem cells resulted in loss of cortical F-actin, reduced cell-cell adhesion, and disrupted localization of adhesion-associated proteins. No evidence of LGR5 coupling to any of the four major subtypes of heterotrimeric G proteins was found. These findings suggest that LGR5 primarily functions via the IQGAP1-Rac1 pathway to strengthen cell-cell adhesion in normal adult crypt stem cells and colon cancer cells.

KW - 7-helix receptor

KW - adhesion

KW - cancer stem cells

KW - G protein-coupled receptor (GPCR)

KW - intestine

U2 - 10.1074/jbc.M117.786798

DO - 10.1074/jbc.M117.786798

M3 - Article

VL - 292

SP - 14989

EP - 15001

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

ER -