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Cell Signal. 2015 Dec;27(12):2579-88. doi: 10.1016/j.cellsig.2015.08.015. Epub 2015 Aug 29.

The adhesion G protein-coupled receptor G2 (ADGRG2/GPR64) constitutively activates SRE and NFκB and is involved in cell adhesion and migration.

Author information

1
Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Denmark; Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, Leiden University, The Netherlands. Electronic address: m.c.peeters@lacdr.leidenuniv.nl.
2
Leiden Academic Centre for Drug Research, Division of Toxicology, Leiden University, The Netherlands.
3
Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, Leiden University, The Netherlands.
4
Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Denmark.

Abstract

Adhesion G protein-coupled receptors (ADGRs) are believed to be activated by auto-proteolytic cleavage of their very large extracellular N-terminal domains normally acting as a negative regulator of the intrinsically constitutively active seven transmembrane domain. ADGRG2 (or GPR64) which originally was described to be expressed in the epididymis and studied for its potential role in male fertility, is highly up-regulated in a number of carcinomas, including breast cancer. Here, we demonstrate that ADGRG2 is a functional receptor, which in transfected HEK293 cells signals with constitutive activity through the adhesion- and migration-related transcription factors serum response element (SRE) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) presumably via coupling to Gα12/13 and Gαq. However, activation of these two pathways appears to occur through distinct molecular activation mechanisms as auto-proteolytic cleavage is essential for SRE activation but not required for NFκB signaling. The overall activation mechanism for ADGRG2 is clearly distinct from the established ADGR activation mechanism as it requires the large extracellular N-terminal domain for proper intracellular signal transduction. Knockdown of ADGRG2 by siRNA in the highly motile breast cancer cell lines Hs578T and MDA-MB-231 resulted in a strong reduction in cell adhesion and subsequent cell migration which was associated with a selective reduction in RelB, an NFκB family member. It is concluded that the adhesion GPCR ADGRG2 is critically involved in the adhesion and migration of certain breast cancer cells through mechanisms including a non-canonical NFkB pathway and that ADGRG2 could be a target for treatment of certain types of cancer.

KEYWORDS:

ADGRG2/GPR64; Activation mechanism; Adhesion G protein-coupled receptor; Breast cancer; Cell adhesion; Cell migration

PMID:
26321231
DOI:
10.1016/j.cellsig.2015.08.015
[Indexed for MEDLINE]

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