title: The adhesion G protein-coupled receptor G2 (ADGRG2/GPR64) constitutively activates SRE and NFκB and is involved in cell adhesion and migration.
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.
authors: 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.
authors: Miriam C
authors: MC
authors: Peeters
authors: Leiden Academic Centre for Drug Research, Division of Toxicology, Leiden University, The Netherlands.
authors: Michiel
authors: M
authors: Fokkelman
authors: Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, Leiden University, The Netherlands.
authors: Bob
authors: B
authors: Boogaard
authors: Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Denmark.
authors: Kristoffer L
authors: KL
authors: Egerod
authors: Leiden Academic Centre for Drug Research, Division of Toxicology, Leiden University, The Netherlands.
authors: Bob
authors: B
authors: van de Water
authors: Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, Leiden University, The Netherlands.
authors: Ad P
authors: AP
authors: IJzerman
authors: Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Denmark.
authors: Thue W
authors: TW
authors: Schwartz
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D059748:Proteolysis; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction; D051841:Transcription Factor RelB / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C105986:ADGRG2 protein, human; D004268:DNA-Binding Proteins; C497593:RELB protein, human; D043562:Receptors, G-Protein-Coupled; C502774:SRE protein, human; D014157:Transcription Factors; D051841:Transcription Factor RelB
keywords: ADGRG2/GPR64; Activation mechanism; Adhesion G protein-coupled receptor; Breast cancer; Cell adhesion; Cell migration