GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion

Shashidhar, Sumana; Lorente, Gustavo; Nagavarapu, Usha; Nelson, April M.; Kuo, Jane; Cummins, Jeramiah; Nikolich, Karoly; Urfer, Roman; Foehr, Erik D

doi:10.1038/sj.onc.1208395

Cited by 149 publications

(134 citation statements)

References 22 publications

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“…54 The purified extracellular domain of GPR56 has also been reported to inhibit cell adhesion, but the mechanism by which this occurs has not been investigated. 55 Our finding that GPR56 interacts with TG2 provides further support for potential roles in cell adhesion (see below). As suggested by motifs in their extracellular segments, other LNB-7TM proteins have also been implicated in cell adhesion.…”

Section: Gpr56 and Tg2 Interactions In Metastasismentioning

confidence: 57%

GPR56 and TG2: Possible Roles in Suppression of Tumor Growth by the Microenvironment

Xu¹,

Hynes²

2007

Cell Cycle

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Metastasis is a complex process that involves multiple levels of cell-cell interaction. Among these interactions, tumor-stroma interactions are being actively investigated. Metastatic cells are hypothesized to show gene expression changes that contribute to their survival and growth at the distant site. Such changes could contribute either to enhancement of growth or to evasion of growth inhibition by the normal tissue environment thus allowing growth as metastases. Our recent report that tumors from highly metastatic melanoma derivatives express low levels of a suppressor of tumor progression, GPR56, is consistent with such a model. GPR56 associates in a complex with Gaq and the tetraspanin protein CD81. We further identified a ligand that interacts with GPR56 in the extracellular matrix (ECM) as TG2, a major crosslinking enzyme in the matrix. TG2 also binds to fibronectin and integrins and affects their cell adhesion functions. TG2 itself has been implicated in suppression of tumor progression; therefore TG2 might serve as a host defense against the invading metastatic cells. The highly metastatic cells may escape from this inhibition by down-regulation of GPR56. Much future work will be needed to test this hypothesis and further our understanding of metastasis in general.

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Section: Gpr56 and Tg2 Interactions In Metastasismentioning

confidence: 57%

GPR56 and TG2: Possible Roles in Suppression of Tumor Growth by the Microenvironment

Xu¹,

Hynes²

2007

Cell Cycle

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“…It should also be noted that the function of GPR56 might be different in different cancer types or stages. In two recent publications, GPR56 has been reported to be up-regulated in gliomas and esophageal squamous cell carcinoma (16,17), although the effects of malignant progression were not examined.…”

Section: Reduction Of Gpr56 Enhances Tumor Growth and Metastasis Inmentioning

confidence: 99%

GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis

Begum

Hearn

et al. 2006

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

249

297

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The survival and growth of tumor cells in a foreign environment is considered a rate-limiting step during metastasis. To identify genes that may be essential for this process, we isolated highly metastatic variants from a poorly metastatic human melanoma cell line and performed expression analyses of metastases and primary tumors from these cells. GPR56 is among the genes markedly downregulated in the metastatic variants. We show that overexpression of GPR56 suppresses tumor growth and metastasis, whereas reduced expression of GPR56 enhances tumor progression. Levels of GPR56 do not correlate with growth rate in vitro, suggesting that GPR56 may mediate growth suppression by interaction with a component in the tumor microenvironment in vivo. We show that GPR56 binds specifically to tissue transglutaminase, TG2, a widespread component of tissue and tumor stroma previously implicated as an inhibitor of tumor progression. We discuss the mechanisms whereby GPR56-TG2 interactions may suppress tumor growth and metastasis. (ii) some of the detached cells enter the circulation via blood vessels or lymphatics (intravasation); (iii) a fraction of the cells in the circulation arrest and transmigrate through blood vessels or lymphatics and invade into a distant tissue or organ (extravasation); (iv) some of the invading cells survive and proliferate in the new environment as metastases. To produce any clinically relevant metastases, a tumor cell must complete all these steps.Abundant clinical and experimental data suggest that the survival and growth step (step iv) is a rate-limiting step during metastasis (1, 2). Frequently, tumor cells are able to enter the circulation and settle in many organs but are not able to proliferate or are only able to proliferate in certain organs. Experimental metastasis assays have been developed to study these steps of metastasis. In these assays, a pool of poorly metastatic tumor cells is injected into the circulation of immunodeficient mice and gives rise to metastases at low frequency. Cells in these rare metastases can be selected from the original pool as variants which, through genetic or epigenetic changes, have gained the ability to invade, survive, and grow in a foreign environment. When these cells are isolated and amplified in vitro, they largely maintain their enhanced metastatic potential. Genes involved in metastasis can then be identified by comparing the gene expression profiles between the highly metastatic variants and the poorly metastatic pool through microarray analyses. With this method, RhoC has previously been discovered to play important roles during melanoma metastasis to lung (3), and a five-gene signature has been discovered to be essential for breast cancer metastasis to bone (4).In this article, we report that a member of a newly described family of G protein-coupled receptors (GPCRs), GPR56, contributes to suppression of melanoma metastasis and tumor growth. This suppression is not cell-autonomous, because cells with altered levels of GPR56 grow at similar rates ...

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“…10) Recently, some reports indicated that GPR56 contributes to tumorigenesis. [12][13][14] Therefore, GPR56 is focused on as a target for anti-cancer drugs. In this research, we generated functional or non-functional monoclonal antibodies against human GPR56 and analyzed the action and signal transduction of GPR56 in human glioma U87-MG cells.…”

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confidence: 99%

Agonistic Antibodies Reveal the Function of GPR56 in Human Glioma U87-MG Cells

Ohta

Sakaguchi

Kobayashi

et al. 2015

Biological & Pharmaceutical Bulletin

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GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) and is highly expressed in parts of tumor cells. The involvement of GPR56 in tumorigenesis has been reported. We generated agonistic monoclonal antibodies against human GPR56 and analyzed the action and signaling pathway of GPR56. The antibodies inhibited cell migration through the Gq and Rho pathway in human glioma U87-MG cells. Coimmunoprecipitation analysis indicated that the interaction between the GPR56 extracellular domain and transmembrane domain was potentiated by agonistic antibodies. These results demonstrated that functional antibodies are invaluable tools for GPCR research and should open a new avenue for therapeutic treatment of tumors.

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GPR56 is a GPCR that is overexpressed in gliomas and functions in tumor cell adhesion

Cited by 149 publications

References 22 publications

GPR56 and TG2: Possible Roles in Suppression of Tumor Growth by the Microenvironment

GPR56 and TG2: Possible Roles in Suppression of Tumor Growth by the Microenvironment

GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis

Agonistic Antibodies Reveal the Function of GPR56 in Human Glioma U87-MG Cells

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