Adhesion-GPCRs in Tumorigenesis

Aust, Gabriela

doi:10.1007/978-1-4419-7913-1_9

Cited by 21 publications

(22 citation statements)

References 89 publications

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“…aGPCRs are misregulated in developmental disorders and many cancers, and some aGPCRs are considered bona fide oncogenes (4)(5)(6)(7). This 33-member subclass of family B GPCRs is distinguished by large extracellular N termini that harbor various adhesion modules and a ∼320-aa GPCR autoproteolysis-inducing (GAIN) domain located proximal to the seven-transmembrane spanning domain (7TM) (8,9).…”

mentioning

confidence: 99%

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Stoveken¹,

Hajduczok²,

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

231

385

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The large class of adhesion G protein-coupled receptors (aGPCRs) bind extracellular matrix or neighboring cell-surface ligands to regulate organ and tissue development through an unknown activation mechanism. We examined aGPCR activation using two prototypical aGPCRs, GPR56 and GPR110. Active dissociation of the noncovalently bound GPR56 or GPR110 extracellular domains (ECDs) from the respective seven-transmembrane (7TM) domains relieved an inhibitory influence and permitted both receptors to activate defined G protein subtypes. After ECD displacement, the newly revealed short N-terminal stalk regions of the 7TM domains were found to be essential for G protein activation. Synthetic peptides comprising these stalks potently activated GPR56 or GPR110 in vitro or in cells, demonstrating that the stalks comprise a tethered agonist that was encrypted within the ECD. Establishment of an aGPCR activation mechanism provides a rational platform for the development of aGPCR synthetic modulators that could find clinical utility toward aGPCR-directed disease.

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mentioning

confidence: 99%

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Stoveken¹,

Hajduczok²,

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

231

385

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“…Adhesion domains, which are thought to have adhesive properties, mainly exist in some adhesion molecules such as integrins, cadherins, and selectins. However, limited studies have shown that adhesion GPCRs are involved in the regulation of cell adhesion, motility, embryonic development, and immune response (12)(13)(14). GPR116, named Ig-hepta in the rat, is a member of the adhesion GPCR family.…”

Section: Introductionmentioning

confidence: 99%

GPR116, an Adhesion G-Protein–Coupled Receptor, Promotes Breast Cancer Metastasis via the Gαq-p63RhoGEF-Rho GTPase Pathway

Tang

Jin

et al. 2013

Cancer Research

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Adhesion G-protein-coupled receptors (GPCR), which contain adhesion domains in their extracellular region, have been found to play important roles in cell adhesion, motility, embryonic development, and immune response. Because most adhesion molecules with adhesion domains have vital roles in cancer metastasis, we speculated that adhesion GPCRs are potentially involved in cancer metastasis. In this study, we identified GPR116 as a novel regulator of breast cancer metastasis through expression and functional screening of the adhesion GPCR family. We found that knockdown of GPR116 in highly metastatic (MDA-MB-231) breast cancer cells suppressed cell migration and invasion. Conversely, ectopic GPR116 expression in poorly metastatic (MCF-7 and Hs578T) cells promoted cell invasion. We further showed that knockdown of GPR116 inhibited breast cancer cell metastasis in two mammary tumor metastasis mouse models. Moreover, GPR116 modulated the formation of lamellipodia and actin stress fibers in cells in a RhoA-and Rac1-dependent manner. At a molecular level, GPR116 regulated cell motility and morphology through the Gaq-p63RhoGEF-RhoA/Rac1 pathway. The biologic significance of GPR116 in breast cancer is substantiated in human patient samples, where GPR116 expression is significantly correlated with breast tumor progression, recurrence, and poor prognosis. These findings show that GPR116 is crucial for the metastasis of breast cancer and support GPR116 as a potential prognostic marker and drug target against metastatic human breast cancer. Cancer Res; 73(20); 6206-18. Ó2013 AACR.

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“…in IRE1 signaling, using cells treated by tunicamycin (0.01 mg/ml during 2 hrs). Moreover, the proliferation rate of glioma cells with mutated IRE1 is decreased in 2 fold [30]. Thus, the blockade of both kinase and endoribonuclease activity of signaling enzyme IRE1 has significant effect on proliferation rate of glioma cells.…”

Section: Cell Culturementioning

confidence: 97%

“…It is overexpressed in various types of tumors and its overexpression is believed to promote cancer progression [26] [27] [28] [29]. ADGRE5 (CD97 antigen) mediates cell-cell interactions, which is involved in angiogenesis and cell migration and is also overexpressed in many cancers [30]. The expression of ADGRE5 gene may play a role in the progression of several types of cancer [31].…”

mentioning

confidence: 99%

Effect of Hypoxia on the Expression of a Subset of Proliferation Related Genes in IRE1 Knockdown U87 Glioma Cells

Tsymbal¹,

Minchenko²,

Hnatiuk³

et al. 2017

ABC

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We have studied the expression of a subset of genes encoding important tumor growth related factors in U87 glioma cells with IRE1 (inositol requiring enzyme-1) knockdown as well as their hypoxic regulation. It was shown that the expression levels of activating transcription factor 6 (ATF6), clusterin (CLU), adhesion G protein-coupled receptor E5 (ADGRE5), transglutaminase 2, C polypeptide (TGM2), leukemia inhibitory factor (LIF), phosphoserine aminotransferase 1 (PSAT1), glyoxalase I (GLO1) and tetraspanin 13 (TSPAN13) are significantly down-regulated in glioma cells with the knockdown of IRE1 signaling enzyme. It was also shown that in glioma cells subjected to hypoxia, the expression levels of PSAT1, TSPAN13, EIF2AK3, and TGM2 genes were up-regulated, whereas the expression of ATF6 gene was down-regulated. At the same time, the expression levels of LIF, CLU, and ADGRE5 genes did not change in response to hypoxic treatment. Furthermore, inhibition of IRE1, a key effector of an unfolded protein response pathway, modified the effect of hypoxia on the expression of most studied genes. Present study demonstrates that IRE1 knockdown down-regulated the expression of most studied genes and modified their hypoxic regulation and that these changes possibly contributed to the suppression of glioma growth in cells without IRE1 signaling enzyme function.

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Adhesion-GPCRs in Tumorigenesis

Cited by 21 publications

References 89 publications

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

GPR116, an Adhesion G-Protein–Coupled Receptor, Promotes Breast Cancer Metastasis via the Gαq-p63RhoGEF-Rho GTPase Pathway

Effect of Hypoxia on the Expression of a Subset of Proliferation Related Genes in IRE1 Knockdown U87 Glioma Cells

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