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

Carmon, KS; Gong, X; Yi, J; Wu, L; Thomas, A; Moore, CM; Masuho, I; Timson, DJ; 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, 292 (36). pp. 14989-15001. ISSN 0021-9258 https://doi.org/10.1074/jbc.M117.786798
SGUL Authors: Moore, Catherine Margaret

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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 up-regulated in many colorectal, hepatocellular, and ovarian cancers. LGR5 activation by R-spondin (RSPO) ligands potentiates Wnt/β-catenin signaling in vitro; however, 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.

Item Type: Article
Additional Information: Final version free via Creative Commons CC-BY license.
Keywords: Biochemistry & Molecular Biology, 06 Biological Sciences, 11 Medical And Health Sciences, 03 Chemical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Journal of Biological Chemistry
ISSN: 0021-9258
Dates:
DateEvent
8 September 2017Published
24 July 2017Published Online
24 July 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
BB/D000394/1Biotechnology and Biological Sciences Research CouncilUNSPECIFIED
URI: http://openaccess.sgul.ac.uk/id/eprint/109102
Publisher's version: https://doi.org/10.1074/jbc.M117.786798

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