Статті в журналах з теми "GPCR Signalling Pathways"
Щоб переглянути інші типи публікацій з цієї теми, перейдіть за посиланням: GPCR Signalling Pathways.
Оформте джерело за APA, MLA, Chicago, Harvard та іншими стилями
Ознайомтеся з топ-50 статей у журналах для дослідження на тему "GPCR Signalling Pathways".
Біля кожної праці в переліку літератури доступна кнопка «Додати до бібліографії». Скористайтеся нею – і ми автоматично оформимо бібліографічне посилання на обрану працю в потрібному вам стилі цитування: APA, MLA, «Гарвард», «Чикаго», «Ванкувер» тощо.
Також ви можете завантажити повний текст наукової публікації у форматі «.pdf» та прочитати онлайн анотацію до роботи, якщо відповідні параметри наявні в метаданих.
Переглядайте статті в журналах для різних дисциплін та оформлюйте правильно вашу бібліографію.
1
Mohamed, Raafat, Reearna Janke, Wanru Guo, Yingnan Cao, Ying Zhou, Wenhua Zheng, Hossein Babaahmadi-Rezaei, Suowen Xu, Danielle Kamato, and Peter J. Little. "GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species." Vascular Biology 1, no. 1 (August 14, 2019): R1—R11. http://dx.doi.org/10.1530/vb-18-0004.
Повний текст джерелаАнотація:
The discovery and extension of G-protein-coupled receptor (GPCR) transactivation-dependent signalling has enormously broadened the GPCR signalling paradigm. GPCRs can transactivate protein tyrosine kinase receptors (PTKRs) and serine/threonine kinase receptors (S/TKRs), notably the epidermal growth factor receptor (EGFR) and transforming growth factor-β type 1 receptor (TGFBR1), respectively. Initial comprehensive mechanistic studies suggest that these two transactivation pathways are distinct. Currently, there is a focus on GPCR inhibitors as drug targets, and they have proven to be efficacious in vascular diseases. With the broadening of GPCR transactivation signalling, it is therefore important from a therapeutic perspective to find a common transactivation pathway of EGFR and TGFBR1 that can be targeted to inhibit complex pathologies activated by the combined action of these receptors. Reactive oxygen species (ROS) are highly reactive molecules and they act as second messengers, thus modulating cellular signal transduction pathways. ROS are involved in different mechanisms of GPCR transactivation of EGFR. However, the role of ROS in GPCR transactivation of TGFBR1 has not yet been studied. In this review, we will discuss the involvement of ROS in GPCR transactivation-dependent signalling.
2
Ellisdon, Andrew M., and Michelle L. Halls. "Compartmentalization of GPCR signalling controls unique cellular responses." Biochemical Society Transactions 44, no. 2 (April 11, 2016): 562–67. http://dx.doi.org/10.1042/bst20150236.
Повний текст джерелаАнотація:
With >800 members, G protein-coupled receptors (GPCRs) are the largest class of cell-surface signalling proteins, and their activation mediates diverse physiological processes. GPCRs are ubiquitously distributed across all cell types, involved in many diseases and are major drug targets. However, GPCR drug discovery is still characterized by very high attrition rates. New avenues for GPCR drug discovery may be provided by a recent shift away from the traditional view of signal transduction as a simple chain of events initiated from the plasma membrane. It is now apparent that GPCR signalling is restricted to highly organized compartments within the cell, and that GPCRs activate distinct signalling pathways once internalized. A high-resolution understanding of how compartmentalized signalling is controlled will probably provide unique opportunities to selectively and therapeutically target GPCRs.
3
Liu, Ying, Yang Yang, Richard Ward, Su An, Xiao-Xi Guo, Wei Li, and Tian-Rui Xu. "Biased signalling: the instinctive skill of the cell in the selection of appropriate signalling pathways." Biochemical Journal 470, no. 2 (August 20, 2015): 155–67. http://dx.doi.org/10.1042/bj20150358.
Повний текст джерелаАнотація:
GPCRs (G-protein-coupled receptors) are members of a family of proteins which are generally regarded as the largest group of therapeutic drug targets. Ligands of GPCRs do not usually activate all cellular signalling pathways linked to a particular seven-transmembrane receptor in a uniform manner. The fundamental idea behind this concept is that each ligand has its own ability, while interacting with the receptor, to activate different signalling pathways (or a particular set of signalling pathways) and it is this concept which is known as biased signalling. The importance of biased signalling is that it may selectively activate biological responses to favour therapeutically beneficial signalling pathways and to avoid adverse effects. There are two levels of biased signalling. First, bias can arise from the ability of GPCRs to couple to a subset of the available G-protein subtypes: Gαs, Gαq/11, Gαi/o or Gα12/13. These subtypes produce the diverse effects of GPCRs by targeting different effectors. Secondly, biased GPCRs may differentially activate G-proteins or β-arrestins. β-Arrestins are ubiquitously expressed and function to terminate or inhibit classic G-protein signalling and initiate distinct β-arrestin-mediated signalling processes. The interplay of G-protein and β-arrestin signalling largely determines the cellular consequences of the administration of GPCR-targeted drugs. In the present review, we highlight the particular functionalities of biased signalling and discuss its biological effects subsequent to GPCR activation. We consider that biased signalling is potentially allowing a choice between signalling through ‘beneficial’ pathways and the avoidance of ‘harmful’ ones.
4
Bhattacharya, M., A. V. Babwah, and S. S. G. Ferguson. "Small GTP-binding protein-coupled receptors." Biochemical Society Transactions 32, no. 6 (October 26, 2004): 1040–44. http://dx.doi.org/10.1042/bst0321040.
Повний текст джерелаАнотація:
Heterotrimeric GPCRs (G-protein-coupled receptors) form the largest group of integral membrane receptor proteins and mediate diverse physiological processes. In addition to signalling via heterotrimeric G-proteins, GPCRs can also signal by interacting with various small G-proteins to regulate downstream effector pathways. The small G-protein superfamily is structurally classified into at least five families: the Ras, Rho/Rac/cdc42, Rab, Sar1/Arf and Ran families. They are monomeric G-proteins with molecular masses over the range 20–30 kDa, which function as molecular switches to control many eukaryotic cell functions. Several studies have provided evidence of crosstalk between GPCRs and small G-proteins. It is well documented that GPCR signalling through heterotrimeric G-proteins can lead to the activation of Ras and Rho GTPases. In addition, RhoA, Rabs, ARFs and ARF GEFs (guanine nucleotide-exchange factors) can associate directly with GPCRs, and GPCRs may also function as GEFs for small GTPases. In this review, we summarize the recent progress made in understanding the interaction between GPCRs and small GTPases, focusing on understanding how the association of small G-proteins with GPCRs and GPCR-regulatory proteins may influence GPCR signalling and intracellular trafficking.
5
Mary, Sophie, Jean-Alain Fehrentz, Marjorie Damian, Pascal Verdié, Jean Martinez, Jacky Marie, and Jean-Louis Banères. "How ligands and signalling proteins affect G-protein-coupled receptors' conformational landscape." Biochemical Society Transactions 41, no. 1 (January 29, 2013): 144–47. http://dx.doi.org/10.1042/bst20120267.
Повний текст джерелаАнотація:
The dynamic character of GPCRs (G-protein-coupled receptors) is essential to their function. However, the details of how ligands and signalling proteins stabilize a receptor conformation to trigger the activation of a given signalling pathway remain largely unexplored. Multiple data, including recent results obtained with the purified ghrelin receptor, suggest a model where ligand efficacy and functional selectivity are directly related to different receptor conformations. Importantly, distinct effector proteins (G-proteins and arrestins) as well as ligands are likely to affect the conformational landscape of GPCRs in different manners, as we show with the isolated ghrelin receptor. Such modulation of the GPCR conformational landscape by pharmacologically distinct ligands and effector proteins has major implications for the design of new drugs that activate specific signalling pathways.
6
Kamato, Danielle, Mai Gabr, Hirushi Kumarapperuma, Zheng J. Chia, Wenhua Zheng, Suowen Xu, Narin Osman та Peter J. Little. "Gαq Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells". International Journal of Molecular Sciences 23, № 22 (20 листопада 2022): 14425. http://dx.doi.org/10.3390/ijms232214425.
Повний текст джерелаАнотація:
Aims: G protein-coupled receptor (GPCR) transactivation of kinase receptors greatly expands the actions attributable to GPCRs. Thrombin, via its cognate GPCR, protease-activated receptor (PAR)-1, transactivates tyrosine and serine/threonine kinase receptors, specifically the epidermal growth factor receptor and transforming growth factor-β receptor, respectively. PAR-1 transactivation-dependent signalling leads to the modification of lipid-binding proteoglycans involved in the retention of lipids and the development of atherosclerosis. The mechanisms of GPCR transactivation of kinase receptors are distinct. We aimed to investigate the role of proximal G proteins in transactivation-dependent signalling. Main Methods: Using pharmacological and molecular approaches, we studied the role of the G⍺ subunits, G⍺q and G⍺11, in the context of PAR-1 transactivation-dependent signalling leading to proteoglycan modifications. Key Findings: Pan G⍺q subunit inhibitor UBO-QIC/FR900359 inhibited PAR-1 transactivation of kinase receptors and proteoglycans modification. The G⍺q/11 inhibitor YM254890 did not affect PAR-1 transactivation pathways. Molecular approaches revealed that of the two highly homogenous G⍺q members, G⍺q and G⍺11, only the G⍺q was involved in regulating PAR-1 mediated proteoglycan modification. Although G⍺q and G⍺11 share approximately 90% homology at the protein level, we show that the two isoforms exhibit different functional roles. Significance: Our findings may be extrapolated to other GPCRs involved in vascular pathology and highlight the need for novel pharmacological tools to assess the role of G proteins in GPCR signalling to expand the preeminent position of GPCRs in human therapeutics.
7
Gorvin, Caroline M. "Insights into calcium-sensing receptor trafficking and biased signalling by studies of calcium homeostasis." Journal of Molecular Endocrinology 61, no. 1 (July 2018): R1—R12. http://dx.doi.org/10.1530/jme-18-0049.
Повний текст джерелаАнотація:
The calcium-sensing receptor (CASR) is a class C G-protein-coupled receptor (GPCR) that detects extracellular calcium concentrations, and modulates parathyroid hormone secretion and urinary calcium excretion to maintain calcium homeostasis. The CASR utilises multiple heterotrimeric G-proteins to mediate signalling effects including activation of intracellular calcium release; mitogen-activated protein kinase (MAPK) pathways; membrane ruffling; and inhibition of cAMP production. By studying germline mutations in the CASR and proteins within its signalling pathway that cause hyper- and hypocalcaemic disorders, novel mechanisms governing GPCR signalling and trafficking have been elucidated. This review focusses on two recently described pathways that provide novel insights into CASR signalling and trafficking mechanisms. The first, identified by studying a CASR gain-of-function mutation that causes autosomal dominant hypocalcaemia (ADH), demonstrated a structural motif located between the third transmembrane domain and the second extracellular loop of the CASR that mediates biased signalling by activating a novel β-arrestin-mediated G-protein-independent pathway. The second, in which the mechanism by which adaptor protein-2 σ-subunit (AP2σ) mutations cause familial hypocalciuric hypercalcaemia (FHH) was investigated, demonstrated that AP2σ mutations impair CASR internalisation and reduce multiple CASR-mediated signalling pathways. Furthermore, these studies showed that the CASR can signal from the cell surface using multiple G-protein pathways, whilst sustained signalling is mediated only by the Gq/11 pathway. Thus, studies of FHH- and ADH-associated mutations have revealed novel steps by which CASR mediates signalling and compartmental bias, and these pathways could provide new targets for therapies for patients with calcaemic disorders.
8
Hart, Stefan, Oliver M. Fischer, Norbert Prenzel, Esther Zwick-Wallasch, Matthias Schneider, Lothar Hennighausen, and Axel Ullrich. "GPCR-induced migration of breast carcinoma cells depends on both EGFR signal transactivation and EGFR-independent pathways." Biological Chemistry 386, no. 9 (September 1, 2005): 845–55. http://dx.doi.org/10.1515/bc.2005.099.
Повний текст джерелаАнотація:
Abstract The epidermal growth factor receptor (EGFR) plays a key role in the regulation of important cellular processes under normal and pathophysiological conditions such as cancer. In human mammary carcinomas the EGFR is involved in regulating cell growth, survival, migration and metastasis and its activation correlates with the lack of response in hormone therapy. Here, we demonstrate in oestrogen receptor-positive and -negative human breast cancer cells and primary mammary epithelial cells a cross-communication between G protein-coupled receptors (GPCRs) and the EGFR. We present evidence that specific inhibition of ADAM15 or TACE blocks GPCR-induced and proHB-EGF-mediated EGFR tyrosine phosphorylation, downstream mitogenic signalling and cell migration. Notably, activation of the PI3K downstream mediator PKB/Akt by GPCR ligands involves the activity of sphingosine kinase (SPHK) and is independent of EGFR signal transactivation. We conclude that GPCR-induced chemotaxis of breast cancer cells is mediated by EGFR-dependent and -independent signalling pathways, with both parallel pathways having to act in concert to achieve a complete migratory response.
9
Fischer, O. M., S. Hart, A. Gschwind, and A. Ullrich. "EGFR signal transactivation in cancer cells." Biochemical Society Transactions 31, no. 6 (December 1, 2003): 1203–8. http://dx.doi.org/10.1042/bst0311203.
Повний текст джерелаАнотація:
The EGFR (epidermal growth factor receptor) plays a key role in the regulation of essential normal cellular processes and in the pathophysiology of hyperproliferative diseases such as cancer. Recent investigations have demonstrated that GPCRs (G-protein-coupled receptors) are able to utilize the EGFR as a downstream signalling partner in the generation of mitogenic signals. This cross-talk mechanism combines the broad diversity of GPCRs with the signalling capacities of the EGFR and has emerged as a general concept in a multitude of cell types. The molecular mechanisms of EGFR signal transactivation involve processing of transmembrane growth factor precursors by metalloproteases which have been recently identified as members of the ADAM (adisintegrin and metalloprotease) family of zinc-dependent proteases. Subsequently, the EGFR transmits signals to prominent downstream pathways, such as mitogen-activated protein kinases, the phosphoinositide 3-kinase/Akt pathway and modulation of ion channels. Analysis of GPCR-induced EGFR activation in more than 60 human carcinoma cell lines derived from different tissues has demonstrated the broad relevance of this signalling mechanism in cancer. Moreover, EGFR signal transactivation was linked to diverse biological processes in human cancer cells, such as cell proliferation, migration and anti-apoptosis. Together with investigations revealing the importance of this GPCR–EGFR cross-talk mechanism in cardiac hypertrophy, Helicobacter pylori-induced pathophysiological processes and cystic fibrosis, these findings support an important role for GPCR ligand-dependent EGFR signal transactivation in diverse pathophysiological disorders.
10
WERRY, Tim D., Graeme F. WILKINSON, and Gary B. WILLARS. "Mechanisms of cross-talk between G-protein-coupled receptors resulting in enhanced release of intracellular Ca2+." Biochemical Journal 374, no. 2 (September 1, 2003): 281–96. http://dx.doi.org/10.1042/bj20030312.
Повний текст джерелаАнотація:
Alteration in [Ca2+]i (the intracellular concentration of Ca2+) is a key regulator of many cellular processes. To allow precise regulation of [Ca2+]i and a diversity of signalling by this ion, cells possess many mechanisms by which they are able to control [Ca2+]i both globally and at the subcellular level. Among these are many members of the superfamily of GPCRs (G-protein-coupled receptors), which are characterized by the presence of seven transmembrane domains. Typically, those receptors able to activate PLC (phospholipase C) enzymes cause release of Ca2+ from intracellular stores and influence Ca2+ entry across the plasma membrane. It has been well documented that Ca2+ signalling by one type of GPCR can be influenced by stimulation of a different type of GPCR. Indeed, many studies have demonstrated heterologous desensitization between two different PLC-coupled GPCRs. This is not surprising, given our current understanding of negative-feedback regulation and the likely shared components of the signalling pathway. However, there are also many documented examples of interactions between GPCRs, often coupling preferentially to different signalling pathways, which result in a potentiation of Ca2+ signalling. Such interactions have important implications for both the control of cell function and the interpretation of in vitro cell-based assays. However, there is currently no single mechanism that adequately accounts for all examples of this type of cross-talk. Indeed, many studies either have not addressed this issue or have been unable to determine the mechanism(s) involved. This review seeks to explore a range of possible mechanisms to convey their potential diversity and to provide a basis for further experimental investigation.
11
Chen, Siyun, Tamar Getter, David Salom, Di Wu, Daniel Quetschlich, Dror S. Chorev, Krzysztof Palczewski, and Carol V. Robinson. "Capturing a rhodopsin receptor signalling cascade across a native membrane." Nature 604, no. 7905 (April 6, 2022): 384–90. http://dx.doi.org/10.1038/s41586-022-04547-x.
Повний текст джерелаАнотація:
AbstractG protein-coupled receptors (GPCRs) are cell-surface receptors that respond to various stimuli to induce signalling pathways across cell membranes. Recent progress has yielded atomic structures of key intermediates1,2 and roles for lipids in signalling3,4. However, capturing signalling events of a wild-type receptor in real time, across a native membrane to its downstream effectors, has remained elusive. Here we probe the archetypal class A GPCR, rhodopsin, directly from fragments of native disc membranes using mass spectrometry. We monitor real-time photoconversion of dark-adapted rhodopsin to opsin, delineating retinal isomerization and hydrolysis steps, and further showing that the reaction is significantly slower in its native membrane than in detergent micelles. Considering the lipids ejected with rhodopsin, we demonstrate that opsin can be regenerated in membranes through photoisomerized retinal–lipid conjugates, and we provide evidence for increased association of rhodopsin with unsaturated long-chain phosphatidylcholine during signalling. Capturing the secondary steps of the signalling cascade, we monitor light activation of transducin (Gt) through loss of GDP to generate an intermediate apo-trimeric G protein, and observe Gαt•GTP subunits interacting with PDE6 to hydrolyse cyclic GMP. We also show how rhodopsin-targeting compounds either stimulate or dampen signalling through rhodopsin–opsin and transducin signalling pathways. Our results not only reveal the effect of native lipids on rhodopsin signalling and regeneration but also enable us to propose a paradigm for GPCR drug discovery in native membrane environments.
12
von Zastrow, M. "Role of endocytosis in signalling and regulation of G-protein-coupled receptors." Biochemical Society Transactions 29, no. 4 (August 1, 2001): 500–504. http://dx.doi.org/10.1042/bst0290500.
Повний текст джерелаАнотація:
Many G-protein-coupled receptors (GPCRs) undergo agonist-induced endocytosis. Endocytosis contributes to distinct processes that regulate the number and functional activity of receptors present in the plasma membrane, contributing to the well described processes of receptor sequestration and down-regulation. Emerging evidence suggests additional functions of endocytosis in mediating GPCR signalling via certain effector pathways, such as mitogen-activated protein kinase modules. The diverse functions of endocytosis raise fundamental questions about the nature of the vesicular carriers and membrane pathways that mediate the endocytic trafficking of specific GPCRs. Insights into the biochemical and functional properties of endocytic vesicles containing internalized opioid and adrenergic receptors will be discussed. Progress towards understanding the mechanisms that control the specificity with which distinct GPCRs are sorted to specialized sub-populations of endocytic vesicles will be highlighted.
13
Gao, Zhengyin, Weng I. Lei, and Leo Tsz On Lee. "The Role of Neuropeptide-Stimulated cAMP-EPACs Signalling in Cancer Cells." Molecules 27, no. 1 (January 5, 2022): 311. http://dx.doi.org/10.3390/molecules27010311.
Повний текст джерелаАнотація:
Neuropeptides are autocrine and paracrine signalling factors and mainly bind to G protein-coupled receptors (GPCRs) to trigger intracellular secondary messenger release including adenosine 3′, 5′-cyclic monophosphate (cAMP), thus modulating cancer progress in different kind of tumours. As one of the downstream effectors of cAMP, exchange proteins directly activated by cAMP (EPACs) play dual roles in cancer proliferation and metastasis. More evidence about the relationship between neuropeptides and EPAC pathways have been proposed for their potential role in cancer development; hence, this review focuses on the role of neuropeptide/GPCR system modulation of cAMP/EPACs pathways in cancers. The correlated downstream pathways between neuropeptides and EPACs in cancer cell proliferation, migration, and metastasis is discussed to glimmer the direction of future research.
14
Al-Janabi, Ismail Ibrahim. "G Protein-Coupled Receptors: Undervalued Targets for Cancer Therapy." Iraqi Journal of Pharmaceutical Sciences ( P-ISSN 1683 - 3597 E-ISSN 2521 - 3512) 31, no. 1 (June 9, 2022): 1–19. http://dx.doi.org/10.31351/vol31iss1pp1-19.
Повний текст джерелаАнотація:
Despite the G protein-coupled receptors (GPCRs) being the largest family of signalling proteins at the surface of cells, their potential to be targeted in cancer therapy is still under-utilised. This review highlights the contribution of these receptors to the process of oncogenesis and points to some likely challenges that might be encountered in targeting them. GPCR-signalling pathways are often complex and can be tissue-specific. Cancer cells hijack these communication networks to their proliferative advantage. The role of selected GPCRs in the different hallmarks of cancer is examined to highlight the complexity of targeting these receptors for therapeutic benefit. Our increasing knowledge of the mechanisms governing the molecular functions of GPCRs may help to identify new targets to treat specific types of cancers.
15
Ladds, Graham, Alan Goddard, and John Davey. "Functional analysis of heterologous GPCR signalling pathways in yeast." Trends in Biotechnology 23, no. 7 (July 2005): 367–73. http://dx.doi.org/10.1016/j.tibtech.2005.05.007.
Повний текст джерела
16
Barclay, Zoë, Louise Dickson, Derek N. Robertson, Melanie S. Johnson, Pamela J. Holland, Roberta Rosie, Liting Sun, Sue Fleetwood-Walker, Eve M. Lutz, and Rory Mitchell. "5-HT2A receptor signalling through phospholipase D1 associated with its C-terminal tail." Biochemical Journal 436, no. 3 (May 27, 2011): 651–60. http://dx.doi.org/10.1042/bj20101844.
Повний текст джерелаАнотація:
The 5-HT2AR (5-hydroxytryptamine-2A receptor) is a GPCR (G-protein-coupled receptor) that is implicated in the actions of hallucinogens and represents a major target of atypical antipsychotic agents. In addition to its classical signalling though PLC (phospholipase C), the receptor can activate several other pathways, including ARF (ADP-ribosylation factor)-dependent activation of PLD (phospholipase D), which appears to be achieved through a mechanism independent of heterotrimeric G-proteins. In the present study we show that wild-type and inactive constructs of PLD1 (but not PLD2) respectively facilitate and inhibit ARF-dependent PLD signalling by the 5-HT2AR. Furthermore we demonstrate that PLD1 specifically co-immunoprecipitates with the receptor and binds to a distal site in GST (glutathione transferase) fusion protein constructs of its C-terminal tail which is distinct from the ARF-interaction site, thereby suggesting the existence of a functional ARF–PLD signalling complex directly associated with this receptor. This reveals the spatial co-ordination of an important GPCR, transducer and effector into a physical complex that is likely to reinforce the impact of receptor activation on a heterotrimeric G-protein-independent signalling pathway. Signalling of this receptor through such non-canonical pathways may be important to its role in particular disorders.
17
Gross, Victoria Elisabeth, and Simone Prömel. "Duale Rezeptorsignale: Wie setzen Adhäsions-GPCR Signale in Funktion um?" BIOspektrum 27, no. 5 (September 2021): 488–90. http://dx.doi.org/10.1007/s12268-021-1625-1.
Повний текст джерелаАнотація:
AbstractAdhesion GPCR are exceptional receptors due to their functional and structural diversity. A key to their function/signalling, setting them apart from other GPCR, is their extraordinarily large, complex N terminus, via which they mediate different molecular mechanisms and integrate diverse biological functions. Here, we discuss dual modes of adhesion GPCR action and how they translate into physiological functions: activation of G protein pathways and signals solely elicited by the N terminus.
18
Pfleger, K. D. G., M. B. Dalrymple, J. R. Dromey та K. A. Eidne. "Monitoring interactions between G-protein-coupled receptors and β-arrestins". Biochemical Society Transactions 35, № 4 (20 липня 2007): 764–66. http://dx.doi.org/10.1042/bst0350764.
Повний текст джерелаАнотація:
β-Arrestins 1 and 2 are ubiquitously expressed intracellular adaptor and scaffolding proteins that play important roles in GPCR (G-protein-coupled receptor) desensitization, internalization, intracellular trafficking and G-protein-independent signalling. Recent developments in BRET (bioluminescence resonance energy transfer) technology enable novel insights to be gained from real-time monitoring of GPCR–β-arrestin complexes in live cells for prolonged periods. In concert with confocal microscopy, assays for studying internalization and recycling kinetics such as ELISAs, and techniques for measuring downstream signalling pathways such as those involving MAPKs (mitogen-activated protein kinases), investigators can now use a range of experimental tools to elucidate the ever-expanding roles of β-arrestins in mediating GPCR function.
19
Sposini, Silvia, and Aylin C. Hanyaloglu. "Driving gonadotrophin hormone receptor signalling: the role of membrane trafficking." Reproduction 156, no. 6 (December 2018): R195—R208. http://dx.doi.org/10.1530/rep-18-0423.
Повний текст джерелаАнотація:
Our understanding of G protein-coupled receptor (GPCR) signalling has significantly evolved over the past decade, whereby signalling not only occurs from the plasma membrane but continues, or is reactivated, following internalisation in to endosomal compartments. The spatial organisation of GPCRs is thus essential to decode dynamic and complex signals and to activate specific downstream pathways that elicit the appropriate cellular response. For the gonadotrophin hormone receptors, membrane trafficking has been demonstrated to play a significant role in regulating its signal activity that in turn would impact at physiological and even pathophysiological level. Here, we will describe the developments in our understanding of the role of ‘location’ in gonadotrophin hormone receptor signalling, and how these receptors have unveiled fundamental mechanisms of signal regulation likely to be pertinent for other GPCRs. We will also discuss the potential impact of spatially controlled gonadotrophin hormone receptor signalling in both health and disease, and the therapeutic possibilities this new understanding of these receptors, so key in reproduction, offers.
20
Capper, Michael J., and Daniel Wacker. "How the ubiquitous GPCR receptor family selectively activates signalling pathways." Nature 558, no. 7711 (June 2018): 529–30. http://dx.doi.org/10.1038/d41586-018-05503-4.
Повний текст джерела
21
Alaridah, Nader, Nataliya Lutay, Erik Tenland, Anna Rönnholm, Oskar Hallgren, Manoj Puthia, Gunilla Westergren-Thorsson, and Gabriela Godaly. "Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs." Journal of Innate Immunity 9, no. 3 (December 24, 2016): 318–29. http://dx.doi.org/10.1159/000453454.
Повний текст джерелаАнотація:
Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.
22
Baker, Jillian G., and Stephen J. Hill. "Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates." Trends in Pharmacological Sciences 28, no. 8 (August 2007): 374–81. http://dx.doi.org/10.1016/j.tips.2007.06.011.
Повний текст джерела
23
Deupi, Xavier, Jörg Standfuss, and Gebhard Schertler. "Conserved activation pathways in G-protein-coupled receptors." Biochemical Society Transactions 40, no. 2 (March 21, 2012): 383–88. http://dx.doi.org/10.1042/bst20120001.
Повний текст джерелаАнотація:
GPCRs (G-protein-coupled receptors) are seven-transmembrane helix proteins that transduce exogenous and endogenous signals to modulate the activity of downstream effectors inside the cell. Despite the relevance of these proteins in human physiology and pharmaceutical research, we only recently started to understand the structural basis of their activation mechanism. In the period 2008–2011, nine active-like structures of GPCRs were solved. Among them, we have determined the structure of light-activated rhodopsin with all the features of the active metarhodopsin-II, which represents so far the most native-like model of an active GPCR. This structure, together with the structures of other inactive, intermediate and active states of rhodopsin constitutes a unique structural framework on which to understand the conserved aspects of the activation mechanism of GPCRs. This mechanism can be summarized as follows: retinal isomerization triggers a series of local structural changes in the binding site that are amplified into three intramolecular activation pathways through TM (transmembrane helix) 5/TM3, TM6 and TM7/TM2. Sequence analysis strongly suggests that these pathways are conserved in other GPCRs. Differential activation of these pathways by ligands could be translated into the stabilization of different active states of the receptor with specific signalling properties.
24
Alloatti, G., G. Montrucchio, G. Lembo та E. Hirsch. "Phosphoinositide 3-kinase γ: kinase-dependent and -independent activities in cardiovascular function and disease". Biochemical Society Transactions 32, № 2 (1 квітня 2004): 383–86. http://dx.doi.org/10.1042/bst0320383.
Повний текст джерелаАнотація:
Cardiac function is controlled by GPCRs (G-protein-coupled receptors) which exert their function by triggering numerous signalling pathways, including the activation of PI3K (phosphoinositide 3-kinase). The GPCR-activated PI3Kγ is weakly expressed in the heart, but the deletion of its expression in mice causes remarkable phenotypes. Indeed, the lack of PI3Kγ does not modify heart rate and blood pressure, but does increase contractility, particularly in response to stimuli that enhance cardiac contractile force, such as catecholamines. Consistently, treatment of mutant cardiomyocytes with β-adrenergic agonists causes an abnormal increase in the elevation of cAMP production. On the other hand, PI3Kγ appears to play a role in mediating the contractile depression exerted by other GPCR agonists, such as PAF (platelet-activating factor), that are released in pathological conditions, such as after an ischaemic insult. The receptor for PAF coupled to Gi activates PI3Kγ, which, in turn, is essential to promote Akt phosphorylation, NOSIII (nitric oxide synthase isoform III) activation and the production of nitric oxide, a well characterized cardiodepressing agent. As a whole, PI3Kγ appears to negatively control cardiac contractility through different signalling mechanisms, thus becoming a possible drug target for the treatment of critical human cardiac pathologies, such as infarction or heart failure.
25
Wiseman, Daniel N., Nikita Samra, María Monserrat Román Lara, Samantha C. Penrice, and Alan D. Goddard. "The Novel Application of Geometric Morphometrics with Principal Component Analysis to Existing G Protein-Coupled Receptor (GPCR) Structures." Pharmaceuticals 14, no. 10 (September 23, 2021): 953. http://dx.doi.org/10.3390/ph14100953.
Повний текст джерелаАнотація:
The G protein-coupled receptor (GPCR) superfamily is a large group of membrane proteins which, because of their vast involvement in cell signalling pathways, are implicated in a plethora of disease states and are therefore considered to be key drug targets. Despite advances in techniques to study these receptors, current prophylaxis is often limited due to the challenging nature of their dynamic, complex structures. Greater knowledge and understanding of their intricate structural rearrangements will therefore undoubtedly aid structure-based drug design against GPCRs. Disciplines such as anthropology and palaeontology often use geometric morphometrics to measure variation between shapes and we have therefore applied this technique to analyse GPCR structures in a three-dimensional manner, using principal component analysis. Our aim was to create a novel system able to discriminate between GPCR structures and discover variation between them, correlated with a variety of receptor characteristics. This was conducted by assessing shape changes at the extra- and intracellular faces of the transmembrane helix bundle, analysing the XYZ coordinates of the amino acids at those positions. We have demonstrated that GPCR structures can be classified based on characteristics such as activation state, bound ligands and fusion proteins, with the most significant results focussed at the intracellular face. Conversely, our analyses provide evidence that thermostabilising mutations do not cause significant differences when compared to non-mutated GPCRs. We believe that this is the first time geometric morphometrics has been applied to membrane proteins on this scale, and believe it can be used as a future tool in sense-checking newly resolved structures and planning experimental design.
26
Roberts, Chrissy H., Sander Ouburg, Mark D. Preston, Henry J. C. de Vries, Martin J. Holland, and Servaas A. Morré. "Pathway-Wide Genetic Risks in Chlamydial Infections Overlap between Tissue Tropisms: A Genome-Wide Association Scan." Mediators of Inflammation 2018 (June 3, 2018): 1–9. http://dx.doi.org/10.1155/2018/3434101.
Повний текст джерелаАнотація:
Chlamydia trachomatis is the most commonly diagnosed bacterial sexually transmitted infection and can lead to tubal factor infertility, a disease characterised by fibrosis of the fallopian tubes. Genetic polymorphisms in molecular pathways involving G protein-coupled receptor signalling, the Akt/PI3K cascade, the mitotic cell cycle, and immune response have been identified in association with the development of trachomatous scarring, an ocular form of chlamydia-related fibrotic pathology. In this case-control study, we performed genome-wide association and pathways-based analysis in a sample of 71 Dutch women who attended an STI clinic who were seropositive for Chlamydia trachomatis antibodies and 169 high-risk Dutch women who sought similar health services but who were seronegative. We identified two regions of within-gene SNP association with Chlamydia trachomatis serological response and found that GPCR signalling and cell cycle pathways were also associated with the trait. These pathway-level associations appear to be common to immunological sequelae of chlamydial infections in both ocular and urogenital tropisms. These pathways may be central mediators of human refractoriness to chlamydial diseases.
27
Daly, Carole A., Martine J. Smit, and Bianca Plouffe. "The constitutive activity of the viral-encoded G protein-coupled receptor US28 supports a complex signalling network contributing to cancer development." Biochemical Society Transactions 48, no. 4 (August 11, 2020): 1493–504. http://dx.doi.org/10.1042/bst20190988.
Повний текст джерелаАнотація:
US28 is a viral G protein-coupled receptor (GPCR) encoded by the human cytomegalovirus (HCMV). This receptor, expressed both during lytic replication and viral latency, is required for latency. US28 is binding to a wide variety of chemokines but also exhibits a particularly high constitutive activity robustly modulating a wide network of cellular pathways altering the host cell environment to benefit HCMV infection. Several studies suggest that US28-mediated signalling may contribute to cancer progression. In this review, we discuss the unique structural characteristics that US28 acquired through evolution that confer a robust constitutive activity to this viral receptor. We also describe the wide downstream signalling network activated by this constitutive activation of US28 and discuss how these signalling pathways may promote and support important cellular aspects of cancer.
28
Langer, I., and P. Robberecht. "Molecular mechanisms involved in vasoactive intestinal peptide receptor activation and regulation: current knowledge, similarities to and differences from the A family of G-protein-coupled receptors." Biochemical Society Transactions 35, no. 4 (July 20, 2007): 724–28. http://dx.doi.org/10.1042/bst0350724.
Повний текст джерелаАнотація:
An actual paradigm for activation and regulation of the GPCR (G-protein-coupled receptors)/seven-transmembrane helix family of receptors essentially emerges from extensive studies of the largest family of receptors, the GPCR-A/rhodopsin family. The mechanisms regulating the GPCR-B family signal transduction are less precisely understood due in part to the lack of the conserved signatures of the GPCR-A family (E/DRY, NPXXY) and in part to the absence of a reliable receptor modelling, although some studies suggest that both families share similar features. Here, we try to highlight the current knowledge of the activation and the regulation of the VIP (vasoactive intestinal peptide) receptors, namely VPAC (VIP/pituitary adenylate cyclase-activating peptide receptor) 1 and 2. This includes search for amino acids involved in the stabilization of the receptor active conformation and in coupling to G-proteins, signalling pathways activated in response to VIP, agonist-dependent receptor down-regulation, phosphorylation and internalization as well as pharmacological consequences of receptor hetero-dimerization.
29
Cattaneo, Fabio, Martina Castaldo, Melania Parisi, Raffaella Faraonio, Gabriella Esposito, and Rosario Ammendola. "Formyl Peptide Receptor 1 Modulates Endothelial Cell Functions by NADPH Oxidase-Dependent VEGFR2 Transactivation." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/2609847.
Повний текст джерелаАнотація:
In the vasculature, NADPH oxidase is the main contributor of reactive oxygen species (ROS) which play a key role in endothelial signalling and functions. We demonstrate that ECV304 cells express p47phox, p67phox, and p22phox subunits of NADPH oxidase, as well as formyl peptide receptors 1 and 3 (FPR1/3), which are members of the GPCR family. By RT-PCR, we also detected Flt-1 and Flk-1/KDR in these cells. Stimulation of FPR1 by N-fMLP induces p47phox phosphorylation, which is the crucial event for NADPH oxidase-dependent superoxide production. Transphosphorylation of RTKs by GPCRs is a biological mechanism through which the information exchange is amplified throughout the cell. ROS act as signalling intermediates in the transactivation mechanism. We show that N-fMLP stimulation induces the phosphorylation of cytosolic Y951, Y996, and Y1175 residues of VEGFR2, which constitute the anchoring sites for signalling molecules. These, in turn, activate PI3K/Akt and PLC-γ1/PKC intracellular pathways. FPR1-induced ROS production plays a critical role in this cross-talk mechanism. In fact, inhibition of FPR1 and/or NADPH oxidase functions prevents VEGFR2 transactivation and the triggering of the downstream signalling cascades. N-fMLP stimulation also ameliorates cellular migration and capillary-like network formation ability of ECV304 cells.
30
CHO, Hyeseon, Kathleen HARRISON, Owen SCHWARTZ, and John H. KEHRL. "The aorta and heart differentially express RGS (regulators of G-protein signalling) proteins that selectively regulate sphingosine 1-phosphate, angiotensin II and endothelin-1 signalling." Biochemical Journal 371, no. 3 (May 1, 2003): 973–80. http://dx.doi.org/10.1042/bj20021769.
Повний текст джерелаАнотація:
Normal cardiovascular development and physiology depend in part upon signalling through G-protein-coupled receptors (GPCRs), such as the angiotensin II type 1 (AT1) receptor, sphingosine 1-phosphate (S1P) receptors and endothelin-1 (ET-1) receptor. Since regulator of G-protein signalling (RGS) proteins function as GTPase-activating proteins for the Gα subunit of heterotrimeric G-proteins, these proteins undoubtedly have functional roles in the cardiovascular system. In the present paper, we show that human aorta and heart differentially express RGS1, RGS2, RGS3S (short-form), RGS3L (long-form), PDZ-RGS3 (PDZ domain-containing) and RGS4. The aorta prominently expresses mRNAs for all these RGS proteins except PDZ-RGS3. Various stimuli that are critical for both cardiovascular development and function regulate dynamically the mRNA levels of several of these RGS proteins in primary human aortic smooth muscle cells. Both RGS1 and RGS3 inhibit signalling through the S1P1 (formerly known as EDG-1), S1P2 (formerly known as EDG-5) and S1P3 (formerly known as EDG-3) receptors, whereas RGS2 and RGS4 selectively attenuate S1P2-and S1P3-receptor signalling respectively. All of the tested RGS proteins inhibit AT1-receptor signalling, whereas only RGS3 and, to a lesser extent, RGS4 inhibit ETA-receptor signalling. The conspicuous expression of RGS proteins in the cardiovascular system and their selective effects on relevant GPCR-signalling pathways provide additional evidence that they have functional roles in cardiovascular development and physiology.
31
Masood, Mehar, Madahiah Bint E. Masood, Noor Us Subah, Maria Shabbir, Rehan Zafar Paracha, and Mehak Rafiq. "Investigating isoform switching in RHBDF2 and its role in neoplastic growth in breast cancer." PeerJ 10 (November 25, 2022): e14124. http://dx.doi.org/10.7717/peerj.14124.
Повний текст джерелаАнотація:
Background Breast cancer is the second leading cause of cancer-related deaths globally, and its prevalence rates are increasing daily. In the past, studies predicting therapeutic drug targets for cancer therapy focused on the assumption that one gene is responsible for producing one protein. Therefore, there is always an immense need to find promising and novel anti-cancer drug targets. Furthermore, proteases have an integral role in cell proliferation and growth because the proteolysis mechanism is an irreversible process that aids in regulating cellular growth during tumorigenesis. Therefore, an inactive rhomboid protease known as iRhom2 encoded by the gene RHBDF2 can be considered an important target for cancer treatment. Speculatively, previous studies on gene expression analysis of RHBDF2 showed heterogenous behaviour during tumorigenesis. Consistent with this, several studies have reported the antagonistic role of iRhom2 in tumorigenesis, i.e., either they are involved in negative regulation of EGFR ligands via the ERAD pathway or positively regulate EGFR ligands via the EGFR signalling pathway. Additionally, different opinions suggest iRhom2 mediated cleavage of EGFR ligands takes place TACE dependently or TACE independently. However, reconciling these seemingly opposing roles is still unclear and might be attributed to more than one transcript isoform of iRhom2. Methods To observe the differences at isoform resolution, the current strategy identified isoform switching in RHBDF2 via differential transcript usage using RNA-seq data during breast cancer initiation and progression. Furthermore, interacting partners were found via correlation and enriched to explain their antagonistic role. Results Isoform switching was observed at DCIS, grade 2 and grade 3, from canonical to the cub isoform. Neither EGFR nor ERAD was found enriched. However, pathways leading to TACE-dependent EGFR signalling pathways were more observant, specifically MAPK signalling pathways, GPCR signalling pathways, and toll-like receptor pathways. Nevertheless, it was noteworthy that during CTCs, the cub isoform switches back to the canonical isoform, and the proteasomal degradation pathway and cytoplasmic ribosomal protein pathways were significantly enriched. Therefore, it could be inferred that cub isoform functions during cancer initiation in EGFR signalling. In contrast, during metastasis, where invasion is the primary task, the isoform switches back to the canonical isoform.
32
Rodrigues, A. R., A. M. Gouveia, J. G. Ferreira, and H. Almeida. "ACTH Induces ERK 1/2 Activation in Rat Adrenal Primary Cultures." Microscopy and Microanalysis 14, S3 (September 2008): 101–2. http://dx.doi.org/10.1017/s1431927608089526.
Повний текст джерелаАнотація:
Adrenocorticotropic hormone (ACTH) is the most potent stimulator of adrenal cortex, acting through the Melanocortin-2 receptor (MC2R). ACTH induces secretion of steroid hormones, critical for the normal stress response and plays also an important role on cell proliferation and differentiation. MC2R is a classical G-Protein coupled receptor (GPCR), thus activating Protein Kinase A (PKA). However, many studies suggested a cross-talk between different signalling pathways and a more complex intracellular network. In fact, in adrenocortical Y1 tumour cell line, ACTH may activate Extracellular Regulated Kinases 1/2 (ERK 1/2), which belong to the Mitogen-Activated Protein Kinases (MAPKs) family. In addition, this pathway was implicated in in vivo proliferation and steroidogenesis as shown by our group. In order to further explore and clarify ACTH signalling mechanisms, we made the present work to establish a model of primary cultures of rat adrenal cells.
33
Fok, Christine, Milan Bogosanovic, Madhavi Pandya, Ravindra Telang, Peter R. Thorne, and Srdjan M. Vlajkovic. "Regulator of G Protein Signalling 4 (RGS4) as a Novel Target for the Treatment of Sensorineural Hearing Loss." International Journal of Molecular Sciences 22, no. 1 (December 22, 2020): 3. http://dx.doi.org/10.3390/ijms22010003.
Повний текст джерелаАнотація:
We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the “post-exposure” treatment with adenosine A1R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A1R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A1R activity in the brain. In this study, Wistar rats (6–8 weeks) were exposed to traumatic noise (110 dBSPL, 8–16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR.
34
Chao, Moses V., Rithwick Rajagopal, and Francis S. Lee. "Neurotrophin signalling in health and disease." Clinical Science 110, no. 2 (January 17, 2006): 167–73. http://dx.doi.org/10.1042/cs20050163.
Повний текст джерелаАнотація:
Neurotrophins are a unique family of polypeptide growth factors that influence the proliferation, differentiation, survival and death of neuronal and non-neuronal cells. They are essential for the health and well-being of the nervous system. NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophin-3) and NT-4 (neurotrophin-4) also mediate additional higher-order activities, such as learning, memory and behaviour, in addition to their established functions for cell survival. The effects of neurotrophins depend upon their levels of availability, their affinity of binding to transmembrane receptors and the downstream signalling cascades that are stimulated after receptor activation. Alterations in neurotrophin levels have been implicated in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, as well as psychiatric disorders, including depression and substance abuse. Difficulties in administering trophic factors have led to the consideration of using small molecules, such as GPCR (G-protein-coupled receptor) ligands, which can participate in transactivation events. In this review, we consider the signalling pathways activated by neurotrophins in both health and disease states.
35
Rovira, Xavier, Jean-Philippe Pin, and Jesús Giraldo. "The asymmetric/symmetric activation of GPCR dimers as a possible mechanistic rationale for multiple signalling pathways." Trends in Pharmacological Sciences 31, no. 1 (January 2010): 15–21. http://dx.doi.org/10.1016/j.tips.2009.10.008.
Повний текст джерела
36
Kelly, Eamonn. "Ligand bias at the μ-opioid receptor". Biochemical Society Transactions 41, № 1 (29 січня 2013): 218–24. http://dx.doi.org/10.1042/bst20120331.
Повний текст джерелаАнотація:
Ligand bias refers to the ability of a drug at a receptor to activate selectively particular cell signalling pathways over others, in a way that cannot be explained by traditional models of receptor theory. For a physiologically and therapeutically important GPCR (G-protein-coupled receptor) such as the MOPr (μ-opioid receptor), the role of ligand bias is currently being explored, not only in order to understand the molecular function of this receptor, but also with a view to developing better analgesic drugs with fewer adverse effects. In this short review, the ways to detect and quantify agonist bias at MOPr are discussed, along with the possible significance of MOPr ligand bias in the therapeutic use of opioid drugs. An important conclusion of this work is that attempts to define ligand bias at any GPCR on the basis of the visual inspection of concentration–response curves or comparison of maximum response (Emax) values can be misleading. Instead, reliable estimations of relative agonist efficacy are needed to calculate bias effectively.
37
Zandona, Antonio, Tamara Zorbaz, Katarina Miš, Sergej Pirkmajer, and Maja Katalinić. "Cytotoxicity-related effects of imidazolium and chlorinated bispyridinium oximes in SH-SY5Y cells." Archives of Industrial Hygiene and Toxicology 73, no. 4 (December 1, 2022): 277–84. http://dx.doi.org/10.2478/aiht-2022-73-3688.
Повний текст джерелаАнотація:
Abstract Current research has shown that several imidazolium and chlorinated bispyridinium oximes are cytotoxic and activate different mechanisms or types of cell death. To investigate this further, we analysed interactions between these oximes and acetylcholine receptors (AChRs) and how they affect several signalling pathways to find a relation between the observed toxicities and their effects on these specific targets. Chlorinated bispyridinium oximes caused time-dependent cytotoxicity by inhibiting the phosphorylation of STAT3 and AMPK without decreasing ATP and activated ERK1/2 and p38 MAPK signal cascades. Imidazolium oximes induced a time-independent and significant decrease in ATP and inhibition of the ERK1/2 signalling pathway along with phosphorylation of p38 MAPK, AMPK, and ACC. These pathways are usually triggered by a change in cellular energy status or by external signals, which suggests that oximes interact with some membrane receptors. Interestingly, in silico analysis also indicated that the highest probability of interaction for all of our oximes is with the family of G-coupled membrane receptors (GPCR). Furthermore, our experimental results showed that the tested oximes acted as acetylcholine antagonists for membrane AChRs. Even though oxime interactions with membrane receptors need further research and clarification, our findings suggest that these oximes make promising candidates for the development of specific therapies not only in the field of cholinesterase research but in other fields too, such as anticancer therapy via altering the Ca2+ flux involved in cancer progression.
38
BISOTTO, Sandra, and Elizabeth D. FIXMAN. "Src-family tyrosine kinases, phosphoinositide 3-kinase and Gab1 regulate extracellular signal-regulated kinase 1 activation induced by the type A endothelin-1 G-protein-coupled receptor." Biochemical Journal 360, no. 1 (November 8, 2001): 77–85. http://dx.doi.org/10.1042/bj3600077.
Повний текст джерелаАнотація:
The multisubstrate docking protein, growth-factor-receptor-bound protein 2-associated binder 1 (Gab1), which is phosphorylated on tyrosine residues following activation of receptor tyrosine kinases and cytokine receptors, regulates cell proliferation, survival and epithelial morphogenesis. Gab1 is also tyrosine phosphorylated following activation of G-protein-coupled receptors (GPCRs) where its function is poorly understood. To elucidate the role of Gab1 in GPCR signalling, we investigated the mechanism by which the type A endothelin-1 (ET-1) GPCR induced tyrosine phosphorylation of Gab1. Tyrosine phosphorylation of Gab1 induced by endothelin-1 was inhibited by PP1, a pharmacological inhibitor of Src-family tyrosine kinases. ET-1-induced Gab1 tyrosine phosphorylation was also inhibited by LY294002, which inhibits phosphoinositide 3-kinase (PI 3-kinase) enzymes. Inhibition of Src-family tyrosine kinases or PI 3-kinase also inhibited ET-1-induced activation of the mitogen activated protein kinase family member, extracellular signal-regulated kinase (ERK) 1. Thus we determined whether Gab1 regulated ET-1-induced ERK1 activation. Overexpression of wild-type Gab1 potentiated ET-1-induced activation of ERK1. Structure–function analyses of Gab1 indicated that mutant forms of Gab1 that do not bind the Src homology (SH) 2 domains of the p85 adapter subunit of PI 3-kinase or the SH2-domain-containing protein tyrosine phosphatase 2 (SHP-2) were impaired in their ability to potentiate ET-1-induced ERK1 activation. Taken together, our data indicate that PI 3-kinase and Src-family tyrosine kinases regulate ET-1-induced Gab1 tyrosine phosphorylation, which, in turn, induces ERK1 activation via PI 3-kinase- and SHP-2-dependent pathways.
39
Sandgren, Johanna, Stefan Holm, Ana Maria Marino, Jurate Asmundsson, Pernilla Grillner, Monica Nistér, and Teresita Díaz de Ståhl. "Whole Exome- and mRNA-Sequencing of an AT/RT Case Reveals Few Somatic Mutations and Several Deregulated Signalling Pathways in the Context ofSMARCB1Deficiency." BioMed Research International 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/862039.
Повний текст джерелаАнотація:
Background. AT/RTs are rare aggressive brain tumours, mainly affecting young children. Most cases present with genetic inactivation ofSMARCB1, a core member of the SWI/SNF chromatin-remodeling complex. We have performed whole exome- and mRNA-sequencing on an early onset AT/RT case for detection of genetic events potentially contributing to the disease.Results. Ade novogermline variant inSMARCB1, c.601C>T p.Arg201∗, in combination with somatic deletion of the healthy allele is likely the major tumour causing event. Only seven somatic small scale mutations were discovered (hittingSEPT03, H2BFM, ZIC4, HIST2H2AB, ZIK1, KRTAP6-3, andIFNA8). All were found with subclonal allele frequencies (range 5.7–17%) and none were expressed. However, besidesSMARCB1, candidate genes affected by predicted damaging germline variants that were expressed were detected (KDM5C, NUMA1, andPCM1). Analysis of differently expressed genes revealed many dysregulated pathways in the tumour, such as cell cycle, CXCR4 pathway, GPCR-signalling, and neuronal system.FGFR1, CXCR4, andMDKwere upregulated and may represent possible drug targets.Conclusion. The loss ofSMARCB1function leads to AT/RT development and deregulated genes and pathways. Additional predisposing events may however contribute. Studies utilizing NGS technologies in larger cohorts will probably identify recurrent genetic and epigenetic alterations and molecular subgroups with implications for clinical practice and development of targeted therapies.
40
Nath, D., N. J. Williamson, R. Jarvis, and G. Murphy. "Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase." Journal of Cell Science 114, no. 6 (March 15, 2001): 1213–20. http://dx.doi.org/10.1242/jcs.114.6.1213.
Повний текст джерелаАнотація:
A wide repertoire of transmembrane proteins are proteolytically released from the cell surface by a process known as ‘ectodomain shedding’, under both normal and pathophysiological conditions. Little is known about the physiological mechanisms that regulate this process. As a model system, we have investigated the metalloproteinase-mediated cleavage of the hepatocyte growth factor receptor, Met. We show that epidermal growth factor (EGF) receptor activation, either directly by EGF or indirectly via the G-protein coupled receptor (GPCR) agonist lysophosphatidic acid (LPA), induces cleavage of Met through activation of the Erk MAP kinase signalling cascade. The tyrosine kinase activity of the EGFR was a prerequisite for this stimulation, since treatment of cells with a synthetic inhibitor of this receptor, AG1478, completely abrogated shedding. The metalloproteinase mediating Met cleavage was specifically inhibited by the tissue inhibitor of metalloproteinases (TIMP)-3, but not by TIMP-1 or TIMP-2. Furthermore, the level of Met shedding could be modulated by different cell-matrix interactions. Our results indicate that ectodomain shedding is a highly regulated process that can be stimulated by EGFR signalling pathways and integrin ligation.
41
YOWE, David, Nadine WEICH, Mercy PRABHUDAS, Louis POISSON, Patrick ERRADA, Rosanna KAPELLER, Kan YU, et al. "RGS18 is a myeloerythroid lineage-specific regulator of G-protein-signalling molecule highly expressed in megakaryocytes." Biochemical Journal 359, no. 1 (September 24, 2001): 109–18. http://dx.doi.org/10.1042/bj3590109.
Повний текст джерелаАнотація:
Myelopoiesis and lymphopoiesis are controlled by haematopoietic growth factors, including cytokines, and chemokines that bind to G-protein-coupled receptors (GPCRs). Regulators of G-protein signalling (RGSs) are a protein family that can act as GTPase-activating proteins for Gαi- and Gαq-class proteins. We have identified a new member of the R4 subfamily of RGS proteins, RGS18. RGS18 contains clusters of hydrophobic and basic residues, which are characteristic of an amphipathic helix within its first 33 amino acids. RGS18 mRNA was most highly abundant in megakaryocytes, and was also detected specifically in haematopoietic progenitor and myeloerythroid lineage cells. RGS18 mRNA was not detected in cells of the lymphoid lineage. RGS18 was also highly expressed in mouse embryonic 15-day livers, livers being the principal organ for haematopoiesis at this stage of fetal development. RGS1, RGS2 and RGS16, other members of the R4 subfamily, were expressed in distinct progenitor and mature myeloerythroid and lymphoid lineage blood cells. RGS18 was shown to interact specifically with the Gαi-3 subunit in membranes from K562 cells. Furthermore, overexpression of RGS18 inhibited mitogen-activated-protein kinase activation in HEK-293/chemokine receptor 2 cells treated with monocyte chemotactic protein-1. In yeast cells, RGS18 overexpression complemented a pheromone-sensitive phenotype caused by mutations in the endogeneous yeast RGS gene, SST2. These data demonstrated that RGS18 was expressed most highly in megakaryocytes, and can modulate GPCR pathways in both mammalian and yeast cells in vitro. Hence RGS18 might have an important role in the regulation of megakaryocyte differentiation and chemotaxis.
42
Labani, Nedjma, Florence Gbahou, Marc Noblet, Bernard Masri, Olivier Broussaud, Jianfeng Liu, and Ralf Jockers. "Pistacia vera Extract Potentiates the Effect of Melatonin on Human Melatonin MT1 and MT2 Receptors with Functional Selectivity." Pharmaceutics 15, no. 7 (June 28, 2023): 1845. http://dx.doi.org/10.3390/pharmaceutics15071845.
Повний текст джерелаАнотація:
Melatonin is a tryptophan derivative synthesized in plants and animals. In humans, melatonin acts on melatonin MT1 and MT2 receptors belonging to the G protein-coupled receptor (GPCR) family. Synthetic melatonin receptor agonists are prescribed for insomnia and depressive and circadian-related disorders. Here, we tested 25 commercial plant extracts, reported to have beneficial properties in sleep disorders and anxiety, using cellular assays (2─[125I]iodomelatonin binding, cAMP inhibition, ERK1/2 activation and β-arrestin2 recruitment) in mock-transfected and HEK293 cells expressing MT1 or MT2. Various melatonin receptor-dependent and -independent effects were observed. Extract 18 (Ex18) from Pistacia vera dried fruits stood out with very potent effects in melatonin receptor expressing cells. The high content of endogenous melatonin in Ex18 (5.28 ± 0.46 mg/g extract) is consistent with this observation. Ex18 contains an additional active principle that potentiates the effect of melatonin on Gi protein-dependent pathways but not on β-arrestin2 recruitment. Further active principles potentiating exogenous melatonin were detected in several extracts. In conclusion, we identified plant extracts with various effects in GPCR-based binding and signalling assays and identified high melatonin levels and a melatonin-potentiating activity in Pistacia vera dried fruit extracts that might be of therapeutic potential.
43
Kostenis, Evi. "G Proteins in Drug Screening: From Analysis of Receptor-G Protein Specificity to Manipulation of GPCR-Mediated Signalling Pathways." Current Pharmaceutical Design 12, no. 14 (May 1, 2006): 1703–15. http://dx.doi.org/10.2174/138161206776873734.
Повний текст джерела
44
Kumar, Shree Senthil, Marie-Louise Ward, and Kathleen Grace Mountjoy. "Quantitative high-throughput assay to measure MC4R-induced intracellular calcium." Journal of Molecular Endocrinology 66, no. 4 (May 1, 2021): 285–97. http://dx.doi.org/10.1530/jme-20-0285.
Повний текст джерелаАнотація:
The melanocortin-4 receptor (MC4R), a critical G-protein-coupled receptor (GPCR) regulating energy homeostasis, activates multiple signalling pathways, including mobilisation of intracellular calcium ([Ca2+]i). However, very little is known about the physiological significance of MC4R-induced [Ca2+]i since few studies measure MC4R-induced [Ca2+]i. High-throughput, read-out assays for [Ca2+]i have proven unreliable for overexpressed GPCRs like MC4R, which exhibit low sensitivity mobilising [Ca2+]i. Therefore, we developed, optimised, and validated a robust quantitative high-throughput assay using Fura-2 ratio-metric calcium dye and HEK293 cells stably transfected with MC4R. The quantitation enables direct comparisons between assays and even between different research laboratories. Assay conditions were optimised step-by-step to eliminate interference from stretch-activated receptor increases in [Ca2+]i and to maximise ligand-activated MC4R-induced [Ca2+]i. Calcium imaging was performed using a PheraStar FS multi-well plate reader. Probenecid, included in the buffers to prevent extrusion of Fura-2 dye from cells, was found to interfere with the EGTA-chelation of calcium, required to determine Rmin for quantitation of [Ca2+]i. Therefore, we developed a method to determine Rmin in specific wells without probenecid, which was run in parallel with each assay. The validation of the assay was shown by reproducible α-melanocyte-stimulating hormone (α-MSH) concentration-dependent activation of the stably expressed human MC4R (hMC4R) and mouse MC4R (mMC4R), inducing increases in [Ca2+]i, for three independent experiments. This robust, reproducible, high-throughput assay that quantitatively measures MC4R-induced mobilisation of [Ca2+]i in vitro has potential to advance the development of therapeutic drugs and understanding of MC4R signalling associated with human obesity.
45
Gorvin, Caroline M. "Molecular and clinical insights from studies of calcium-sensing receptor mutations." Journal of Molecular Endocrinology 63, no. 2 (August 2019): R1—R16. http://dx.doi.org/10.1530/jme-19-0104.
Повний текст джерелаАнотація:
Twenty-five years have elapsed since the calcium-sensing receptor (CaSR) was first identified in bovine parathyroid and the receptor is now recognized as a fundamental contributor to extracellular Ca2+ (Ca2+ e) homeostasis, regulating parathyroid hormone release and urinary calcium excretion. The CaSR is a class C G-protein-coupled receptor (GPCR) that is functionally active as a homodimer and couples to multiple G-protein subtypes to activate intracellular signalling pathways. The importance of the CaSR in the regulation of Ca2+ e has been highlighted by the identification of >400 different germline loss- and gain-of-function CaSR mutations that give rise to disorders of Ca2+ e homeostasis. CaSR-inactivating mutations cause neonatal severe hyperparathyroidism, characterised by marked hypercalcaemia, skeletal demineralisation and failure to thrive in early infancy; and familial hypocalciuric hypercalcaemia, an often asymptomatic disorder associated with mild-moderately elevated serum calcium concentrations. Activating mutations are associated with autosomal dominant hypocalcaemia, which is occasionally associated with a Bartter’s-like phenotype. Recent elucidation of the CaSR extracellular domain structure enabled the locations of CaSR mutations to be mapped and has revealed clustering in locations important for structural integrity, receptor dimerisation and ligand binding. Moreover, the study of disease-causing mutations has demonstrated that CaSR signals in a biased manner and have revealed specific residues important for receptor activation. This review presents the current understanding of the genetic landscape of CaSR mutations by summarising findings from clinical and functional studies of disease-associated mutations. It concludes with reflections on how recently uncovered signalling pathways may expand the understanding of calcium homeostasis disorders.
46
González-Guede, I., M. López-Ramos, L. Rodriguez Rodriguez, L. Abasolo, and B. Fernandez. "POS0409 IMPLICATION OF GLYPICANS AND NOTUM IN BONE MARROW MESENCHYMAL STROMAL CELLS DURING OSTEOGENIC DIFFERENTIATION IN OSTEOARTHRITIC DISEASE." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 459.3–460. http://dx.doi.org/10.1136/annrheumdis-2023-eular.6294.
Повний текст джерелаАнотація:
BackgroundOsteoarthritis (OA) is accompanied by an excessive formation of underlying bone caused by homeostatic alterations. It has been described that in OA joints there is an up-regulation of the WNT/β-catenine pathway driving to the differentiation of Mesenchymal Stromal Cells (MSCs) into osteocytes [1]. Glypicans 1-6 act as co-receptors of WNT pathway, improving interactions between molecules [2]. On the other hand, NOTUM plays a role as a negative regulator of the pathway preventing WNT binding to its receptors and favouring the soluble form of Glypicans [3]. All these evidences lead us to think about the importance of Glypicans 1-6 and NOTUM in the osteogenic differentiation of MSCs in OA disease.ObjectivesTo determine the differences at gene and protein levels of Glypicans 1-6 and NOTUM in MSCs between OA patients and controls at baseline and during inducedin vitroosteogenic differentiation.MethodsBone Marrow Mesenchymal Stromal Cells (BM-MSCs) from both, 8 OA patients and 8 healthy donors were isolated from BM samples. BM samples were obtained by joint replacement and traumatic fractures. BM-MSCs were cultured during 21 days with normal culture medium and with osteogenic inducing medium. Cells and supernatant were recovered at 1, 7, 14 and 21 days. Protein levels were determined by ELISA in cells supernatant. Extraction and purification of RNA from cells and cDNA synthesis were performed. Glypicans 1-6 and NOTUM gene-expression was analysed by qPCR and normalized with housekeeping genes β-actin and RNA18S. The data were calculated with the method of fold change (2-ΔΔCt). Statical analysis were performed with GraphPad Prism 8.0. For the detection of outliers, the ROUT method (Q=1%) was used. Data were analyzed using t-test.ResultsThe mRNA levels of cells with normal culture medium were up-regulated in GPC6 (t=7d; p=0,016) in OA patients. During osteogenic differentiation, was observed a statistically significant up-regulation in levels of OA patients vs controls of GPC2 (t=14d; p=0,034), GPC4 (t=14d, p=0,025; t=21d, p=0,017), GPC5 (t=14d, p=0,007), GPC6 (t=14d, p=0,013) andNOTUM(t=14d, p=0,009) and down-regulation of GPC3 (t=7d, p=0,034). In addition, protein levels of NOTUM were lower compared to the control group in OA BM-MSCs (t=1d, p=0,049) and in the differentiation to osteocytes (t=1d, p=0,049; t=7d, p=0,043; t=14d, p=0,016). GPC3 levels were higher OA patients in all the times and in the two conditions (p < 0,0001). In the differentiation, GPC2 were lower (t=7d, p< 0,0001). GPC1, GPC4 and GPC6 were not present in any case.ConclusionOur results evidence a dysregulation in the glypicans in BM-MSCs of OA patients and, specially, during osteogenic differentiation. NOTUM, extracellular negative regulator of the WNT/β-catenine signaling pathway, is decreased at protein level in OA patients, despite the fact that gene expression is elevated. Thus, our data confirm the differences in expression in NOTUM and Glypicans between OA patients and healthy controls. Further studies are needed proposing these molecules, specially NOTUM, as an effective treatment of the disease.References[1]Tornero-Estebanet al., 2015 “Altered Expression” PLoS One.[2]Boudinet al.,2013 “The role” Semin Arthritis Rheum.[3]Nusse R., 2015 “Cell signalling” Nature.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
47
Coquant, G., D. Aguanno, L. Brot, C. Belloir, L. Briand, J. P. Grill, L. De Sordi, S. Thenet, and P. Seksik. "P043 3-oxo-C12:2, a Quorum Sensing molecule from the gut, exerts anti-inflammatory effects through a bitter taste receptor." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i160. http://dx.doi.org/10.1093/ecco-jcc/jjab232.172.
Повний текст джерелаАнотація:
Abstract Background Acyl-Homoserine Lactones (AHLs) are Quorum Sensing molecules involved in the communication network of bacteria and can also have an impact on the host’s cells. We recently showed, in the human gut ecosystem, the presence of AHLs. Among them, we identified one that has never been described: 3-oxo-C12:2. This molecule was decreased in Inflammatory Bowel Disease (IBD) patients, and its presence was correlated to normobiosis. Interestingly, 3-oxo-C12:2 is structurally close to an AHL well described and synthesized by P. aeruginosa, 3-oxo-C12. We intent to describe 3-oxo-C12:2 effects on gut inflammation and to identified which signalling pathways are involved. Given its analogous structure to 3-oxo-C12, we hypothesized that 3-oxo-C12:2 can interact with the same cellular partners, in particular a bitter taste receptor (BTR), called T2R138, which is a GPCR expressed by immune and epithelial gut cells. Methods To test our hypothesis, we used murine macrophages cell line RAW264.7, stimulated by interferon-γ (IFN-γ, 20U/mL) and lipopolysaccharide (LPS, 10ng/mL). Inflammatory response was monitored by measuring cytokine secretion via ELISA We performed a transcriptome analysis to identify inflammatory pathways involved in the effects and analyse pathways by capillary Western blot. Probenecid, a known allosteric inhibitor for T2R138, was used to study T2R138 role in AHL signalling. BTR screening assay was performed to extend search for 3-oxo-C12:2 receptors. Results After LPS/IFN-γ activation, we observed a decrease of secreted TNFα when cells were exposed to 3-oxo-C12:2, in a dose dependent manner: 15μM (-30%, p<0.05), 25μM (-50%, p<0.001) et 50μM (-65%, p<0.0001) while no change were observed in steady state. This reflects an anti-inflammatory effect, in absence of cytotoxicity. By transcriptomic analysis, we identified the JAK-STAT pathway as differentially down-regulated. Exposing cells to 3-oxo-C12:2 prevented JAK1 and STAT1 protein phosphorylation. In addition, the observed anti-inflammatory effects were lost in presence of Probenecid, a T2R138 inhibitor. In a BTR screening assay, we confirmed that 3-oxo-C12:2 activates T2R38, but also five other BTR (T2R13, T2R8, T2R14, T2R1, T2R10). Conclusion 3-oxo-C12:2 exerts a dose dependent anti-inflammatory effect on murine immune cells by preventing the activation of the JAK-STAT pathway. This response is partly mediated by the bitter taste receptor T2R138. This receptor is a potential target of our AHL of interest. Studying the signalling between the receptor and the anti-inflammatory response would allow us to better understand the inter-kingdom dialogue between microbiota involving AHL in IBD.
48
Little, Peter J. "GPCR responses in vascular smooth muscle can occur predominantly through dual transactivation of kinase receptors and not classical Gαq protein signalling pathways". Life Sciences 92, № 20-21 (травень 2013): 951–56. http://dx.doi.org/10.1016/j.lfs.2013.03.017.
Повний текст джерела
49
Raimondi, Francesco, Joshua G. Burkhart, Matthew J. Betts, Robert B. Russell, and Guanming Wu. "Leveraging biochemical reactions to unravel functional impacts of cancer somatic variants affecting protein interaction interfaces." F1000Research 10 (November 3, 2021): 1111. http://dx.doi.org/10.12688/f1000research.74395.1.
Повний текст джерелаАнотація:
Background: Considering protein mutations in their biological context is essential for understanding their functional impact, interpretation of high-dimensional datasets and development of effective targeted therapies in personalized medicine. Methods: We combined the curated knowledge of biochemical reactions from Reactome with the analysis of interaction-mediating 3D interfaces from Mechismo. In addition, we provided a software tool for users to explore and browse the analysis results in a multi-scale perspective starting from pathways and reactions to protein-protein interactions and protein 3D structures. Results: We analyzed somatic mutations from TCGA, revealing several significantly impacted reactions and pathways in specific cancer types. We found examples of genes not yet listed as oncodrivers, whose rare mutations were predicted to affect cancer processes similarly to known oncodrivers. Some identified processes lack any known oncodrivers, which suggests potentially new cancer-related processes (e.g. complement cascade reactions). Furthermore, we found that mutations perturbing certain processes are significantly associated with distinct phenotypes (i.e. survival time) in specific cancer types (e.g. PIK3CA centered pathways in LGG and UCEC cancer types), suggesting the translational potential of our approach for patient stratification. Our analysis also uncovered several druggable processes (e.g. GPCR signalling pathways) containing enriched reactions, providing support for new off-label therapeutic options. Conclusions: In summary, we have established a multi-scale approach to study genetic variants based on protein-protein interaction 3D structures. Our approach is different from previously published studies in its focus on biochemical reactions and can be applied to other data types (e.g. post-translational modifications) collected for many types of disease.
50
Raimondi, Francesco, Joshua G. Burkhart, Matthew J. Betts, Robert B. Russell, and Guanming Wu. "Leveraging biochemical reactions to unravel functional impacts of cancer somatic variants affecting protein interaction interfaces." F1000Research 10 (December 12, 2022): 1111. http://dx.doi.org/10.12688/f1000research.74395.3.
Повний текст джерелаАнотація:
Background: Considering protein mutations in their biological context is essential for understanding their functional impact, interpretation of high-dimensional datasets and development of effective targeted therapies in personalized medicine. Methods: We combined the curated knowledge of biochemical reactions from Reactome with the analysis of interaction-mediating 3D interfaces from Mechismo. In addition, we provided a software tool for users to explore and browse the analysis results in a multi-scale perspective starting from pathways and reactions to protein-protein interactions and protein 3D structures. Results: We analyzed somatic mutations from TCGA, revealing several significantly impacted reactions and pathways in specific cancer types. We found examples of genes not yet listed as oncodrivers, whose rare mutations were predicted to affect cancer processes similarly to known oncodrivers. Some identified processes lack any known oncodrivers, which suggests potentially new cancer-related processes (e.g. complement cascade reactions). Furthermore, we found that mutations perturbing certain processes are significantly associated with distinct phenotypes (i.e. survival time) in specific cancer types (e.g. PIK3CA centered pathways in LGG and UCEC cancer types), suggesting the translational potential of our approach for patient stratification. Our analysis also uncovered several druggable processes (e.g. GPCR signalling pathways) containing enriched reactions, providing support for new off-label therapeutic options. Conclusions: In summary, we have established a multi-scale approach to study genetic variants based on protein-protein interaction 3D structures. Our approach is different from previously published studies in its focus on biochemical reactions and can be applied to other data types (e.g. post-translational modifications) collected for many types of disease.