Adhesion G protein-coupled receptors in glioblastoma

Stephan, Gabriele; Ravn-Boess, Niklas; Placantonakis, Dimitris G.

doi:10.1093/noajnl/vdab046

Cited by 10 publications

(14 citation statements)

References 131 publications

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“…For example, given our discovery that GPR133 is required for GBM growth, engineering inhibitory anti-GPR133 antibodies would lay the foundation for testing effects on tumor biology (21). Alternatively, given the de novo expression of GPR133 in GBM relative to healthy non-neoplastic brain tissue, anti-GPR133 internalizing antibodies could be used to deliver antibody-drug conjugates to GBM cells (21,28,34).…”

Section: Discussionmentioning

confidence: 99%

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Activation of the adhesion GPCR GPR133 (ADGRD1) by antibodies targeting the N-terminus

Stephan

Frenster

Liebscher

et al. 2021

Preprint

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We recently demonstrated that GPR133 (ADGRD1), an adhesion G protein-coupled receptor (aGPCR) whose canonical signaling raises cytosolic cAMP, is necessary for growth of glioblastoma (GBM) and is de novo expressed in GBM relative to normal brain tissue. We showed that dissociation of autoproteolytically generated N-terminal and C-terminal fragments (NTF and CTF) of GPR133 at the plasma membrane promotes receptor activation and increases signaling. Toward developing biologics modulating GPR133 function, we tested antibodies against the N-terminus of GPR133 for effects on receptor signaling. Treatment of HEK293T cells overexpressing GPR133 with such antibodies increased cAMP levels in a concentration-dependent manner. Analysis of supernatants following antibody treatment revealed complexes of the antibodies with the autoproteolytically cleaved NTF of GPR133. Cells expressing a cleavage-deficient mutant GPR133 (H543R) did not respond to antibody stimulation, suggesting that the effect is cleavage-dependent. The antibody-mediated stimulation of wild-type GPR133, but not the cleavage-deficient H543R mutant, was reproducible in patient-derived GBM cells. These findings provide a paradigm for modulation of GPR133 function with biologics and support the hypothesis that NTF-CTF dissociation promotes receptor activation and signaling.

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Section: Discussionmentioning

confidence: 99%

“…Alternatively, given the de novo expression of GPR133 in GBM relative to healthy non-neoplastic brain tissue, anti-GPR133 internalizing antibodies could be used to deliver antibody-drug conjugates to GBM cells (Bayin et al, 2016;Frenster et al, 2020;Stephan, Ravn-Boess, & Placantonakis, 2021).…”

Section: Discussionmentioning

confidence: 99%

Activation of the adhesion GPCR GPR133 (ADGRD1) by antibodies targeting the N-terminus

Stephan

Frenster

Liebscher

et al. 2021

Preprint

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“…Cellular functions of aGPCRs such as cell adhesion, migration, cell polarity, and guidance are highly relevant for tumor cell biology. Consistently, members from all aGPCR groups are associated with cancer, for example, GPR56/ADGRG1, CD97/ADGRE5, GPR133/ADGRD1, ELTD1/ADGRL4, GPR110/ADGRF1, GPR116/ADGRF5, BAI1/ADGRB1, GPR124/ADGRA2, and GPR125/ADGRA3 [161‐167]. For some of these aGPCRs, there is evidence for incorrect expression or changes in receptor activity (e.g., VLGR1/ADGRV [168], GPR133/ADGRD1 [169], and LPHN/ADGRL [170]), whereas for others, detailed knowledge exists about the molecular role they play in tumorigenesis (e.g., CD97/ADGRE5 [34,171,172], ADGRF5/GPR116 [173,174], GPR56/ADGRG1 [51,175,176,177], BAI1/ADRGB1 [178‐180], GPR124/ADGRA2 [181], and GPR125/ADGRA3 [182]).…”

Section: Clinical Aspects Of Agpcr Function and Potential Therapeuticsmentioning

confidence: 99%

A guide to adhesion GPCR research

et al. 2021

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Adhesion G protein‐coupled receptors (aGPCRs) are a class of structurally and functionally highly intriguing cell surface receptors with essential functions in health and disease. Thus, they display a vastly unexploited pharmacological potential. Our current understanding of the physiological functions and signaling mechanisms of aGPCRs form the basis for elucidating further molecular aspects. Combining these with novel tools and methodologies from different fields tailored for studying these unusual receptors yields a powerful potential for pushing aGPCR research from singular approaches toward building up an in‐depth knowledge that will facilitate its translation to applied science. In this review, we summarize the state‐of‐the‐art knowledge on aGPCRs in respect to structure–function relations, physiology, and clinical aspects, as well as the latest advances in the field. We highlight the upcoming most pressing topics in aGPCR research and identify strategies to tackle them. Furthermore, we discuss approaches how to promote, stimulate, and translate research on aGPCRs ‘from bench to bedside’ in the future.

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“…It has been demonstrated that GPCRs bind ligands from the ECM or plasma membrane of adjacent cells, causing conveying cell–cell or cell–matrix interactions [ 47 ]. The activation of a receptor thorough binding with a ligand leads to changes in cellular processes, including cell migration, proliferation, neoangiogenesis and invasion of GBM [ 48 ]. Moreover, GPCR could be targeted for GBM therapies because of their role in controlling tumor pathogenesis through molecular interactions with oncogenic signaling pathways [ 48 ].…”

Section: A Disintegrin and Metalloproteinase (Adam)—general Informationmentioning

confidence: 99%

“…The activation of a receptor thorough binding with a ligand leads to changes in cellular processes, including cell migration, proliferation, neoangiogenesis and invasion of GBM [ 48 ]. Moreover, GPCR could be targeted for GBM therapies because of their role in controlling tumor pathogenesis through molecular interactions with oncogenic signaling pathways [ 48 ]. In addition, several ADAMs are kept in an inactive state via the interaction of a cysteine residue with zinc at the propeptide domain in the metalloproteinase module.…”

Section: A Disintegrin and Metalloproteinase (Adam)—general Informationmentioning

confidence: 99%

A Disintegrin and Metalloproteinase (ADAM) Family: Their Significance in Malignant Tumors of the Central Nervous System (CNS)

Łukaszewicz-Zając

Dulewicz

Mroczko

2021

IJMS

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Despite the considerable advances in diagnostic methods in medicine, central nervous system (CNS) tumors, particularly the most common ones – gliomas–remain incurable, with similar incidence rates and mortality. A growing body of literature has revealed that degradation of the extracellular matrix by matrix metalloproteinases (MMPs) might be involved in the pathogenesis of CNS tumors. However, the subfamily of MMPs, known as disintegrin and metalloproteinase (ADAM) proteins are unique due to both adhesive and proteolytic activities. The objective of our review is to present the role of ADAMs in CNS tumors, particularly their involvement in the development of malignant gliomas. Moreover, we focus on the diagnostic and prognostic significance of selected ADAMs in patients with these neoplasms. It has been proven that ADAM12, ADAMTS4 and 5 are implicated in the proliferation and invasion of glioma cells. In addition, ADAM8 and ADAM19 are correlated with the invasive activity of glioma cells and unfavorable survival, while ADAM9, -10 and -17 are associated with tumor grade and histological type of gliomas and can be used as prognostic factors. In conclusion, several ADAMs might serve as potential diagnostic and prognostic biomarkers as well as therapeutic targets for malignant CNS tumors.However, future research on ADAMs biology should be performed to elucidate new strategies for tumor diagnosis and treatment of patients with these malignancies.

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Adhesion G protein-coupled receptors in glioblastoma

Cited by 10 publications

References 131 publications

Activation of the adhesion GPCR GPR133 (ADGRD1) by antibodies targeting the N-terminus

Activation of the adhesion GPCR GPR133 (ADGRD1) by antibodies targeting the N-terminus

A guide to adhesion GPCR research

A Disintegrin and Metalloproteinase (ADAM) Family: Their Significance in Malignant Tumors of the Central Nervous System (CNS)

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