FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1778048163> ?p ?o ?g. }

• W1778048163 endingPage "23039" @default.
• W1778048163 startingPage "23038" @default.
• W1778048163 abstract "Research on G protein-coupled receptors (GPCRs, 7TM receptors) has attracted remarkable interest throughout the last few decades. They are involved in several human diseases and their accessibility for pharmaceutical intervention has made them the number one drug target [1]. As the de-orphanization of every receptor harbors a potential new therapeutic option, uncharacterized GPCRs are in fact a true treasure chest. While the majority of studies have been performed on Rhodopsin-like GPCRs, the whole class of Adhesion GPCRs (aGPCRs) remained orphan for a long time, even though their involvement in human syndromes and diseases including cancer has been widely demonstrated [2].With up to 6,500 amino acids, aGPCRs are giants among the 7TM receptors. The large modular N terminus in most representatives of this class undergoes an autoproteolytic cleavage event resulting in two functional parts - an N-terminal fragment (NTF) and a C-terminal fragment (CTF) (Figure ​(Figure1).1). This cleavage event takes place at a highly conserved motif within the GPCR proteolytic site (GPS), which is part of a domain common for aGPCRs, the GPCR proteolysis-inducing (GAIN) domain. Several domains (e.g. EGF, leucine-rich domain) within the NTF are the reason that aGPCRs were initially identified as cell differentiation markers and adhesion molecules, while functions as GPCRs was mainly suggested based on sequence homology. Recently, the functional interaction between G proteins and aGPCRs was demonstrated showing that aGPCRs, as other GPCRs, can couple to different G proteins [reviewed in 2].Figure 1Activation mechanism of aGPCRsKnowing the intracellular signaling pathway of the giants formed the basis for examining the activation mechanism. A groundbreaking observation was that receptor mutants lacking the NTF show constitutive activity, leaving two possible explanations: 1) the NTF acts as a tethered inverse agonist or 2) the NTF blocks an encrypted tethered agonist [discussed in 3].A recent study now provides evidences that the N termini of aGPCRs contain their own agonists and self-activate the transmembrane domain upon structural changes of the NTF. Due to the position of this agonistic region at the end of the CTF and its proclaimed piercing interaction with the 7TM, we called the tethered agonist the Stachel sequence - the German word for “stinger” (Figure ​(Figure1)1) [4]. The Stachel region correlates with the last beta-sheet of the proposed crystal structure of the GAIN domain [5]. However, according to this structure, this last beta-sheet lies buried within other beta-sheets giving rise to the question of how the agonist is exposed. Given the cleavage motif as a natural break point, removal of the NTF seems likely, yet it remains to be proven that this actually happens in vivo.There are a number of proteins that bind to the NTF, among them extracellular matrix molecules like collagen and laminin, which do not display characteristic features of an agonist. Collagens and laminins have been shown to modulate G-protein signaling of some aGPCRs. For example, one GPR126 binding partner, laminin 211, inhibits cAMP production under static conditions. However, upon application of shaking or vibration to the cell culture, an increase in cAMP accumulation was observed [6]. Analysis of a corresponding zebrafish model provided evidence that the physiological correlate of this mechanic force would be the polymerization of laminin 211. It is yet unclear whether this mechanic force will lead to the removal of the NTF as a cause of receptor activation. Interestingly, involvement in mechanosensation has also been suggested for other aGPCRs [7].The identification of G-protein coupling as one important signaling pathway of aGPCRs (cis-signaling) and their activation by a tethered agonist mechanism were important steps towards understanding the physiology of this previously enigmatic receptor class. However, the NTF is most likely capable of an independent trans-signaling mediated by cell-cell contacts [reviewed in 3]. The recent discovery of the activation mechanism and metabotropic signal transduction of aGPCRs now allows for rational ligand design and will promote studying the physiology and therapeutic usefulness of this emerging group of GPCRs in many fields including developmental biology, immunology, neurobiology and tumorigenesis." @default.
• W1778048163 created "2016-06-24" @default.
• W1778048163 creator A5007341947 @default.
• W1778048163 creator A5019098595 @default.
• W1778048163 creator A5063460244 @default.
• W1778048163 date "2015-08-06" @default.
• W1778048163 modified "2023-10-16" @default.
• W1778048163 title "How to wake a giant" @default.
• W1778048163 cites W1980022376 @default.
• W1778048163 cites W2021218920 @default.
• W1778048163 cites W2051852715 @default.
• W1778048163 cites W2066517842 @default.
• W1778048163 cites W2111689719 @default.
• W1778048163 cites W2147241078 @default.
• W1778048163 cites W2159319913 @default.
• W1778048163 doi "https://doi.org/10.18632/oncotarget.5112" @default.
• W1778048163 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4695099" @default.
• W1778048163 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26405160" @default.
• W1778048163 hasPublicationYear "2015" @default.
• W1778048163 type Work @default.
• W1778048163 sameAs 1778048163 @default.
• W1778048163 citedByCount "6" @default.
• W1778048163 countsByYear W17780481632016 @default.
• W1778048163 countsByYear W17780481632017 @default.
• W1778048163 countsByYear W17780481632018 @default.
• W1778048163 countsByYear W17780481632019 @default.
• W1778048163 crossrefType "journal-article" @default.
• W1778048163 hasAuthorship W1778048163A5007341947 @default.
• W1778048163 hasAuthorship W1778048163A5019098595 @default.
• W1778048163 hasAuthorship W1778048163A5063460244 @default.
• W1778048163 hasBestOaLocation W17780481631 @default.
• W1778048163 hasConcept C121332964 @default.
• W1778048163 hasConcept C48939323 @default.
• W1778048163 hasConcept C71924100 @default.
• W1778048163 hasConcept C97355855 @default.
• W1778048163 hasConceptScore W1778048163C121332964 @default.
• W1778048163 hasConceptScore W1778048163C48939323 @default.
• W1778048163 hasConceptScore W1778048163C71924100 @default.
• W1778048163 hasConceptScore W1778048163C97355855 @default.
• W1778048163 hasIssue "27" @default.
• W1778048163 hasLocation W17780481631 @default.
• W1778048163 hasLocation W17780481632 @default.
• W1778048163 hasLocation W17780481633 @default.
• W1778048163 hasLocation W17780481634 @default.
• W1778048163 hasOpenAccess W1778048163 @default.
• W1778048163 hasPrimaryLocation W17780481631 @default.
• W1778048163 hasRelatedWork W1489783725 @default.
• W1778048163 hasRelatedWork W1506200166 @default.
• W1778048163 hasRelatedWork W2039318446 @default.
• W1778048163 hasRelatedWork W2048182022 @default.
• W1778048163 hasRelatedWork W2080531066 @default.
• W1778048163 hasRelatedWork W2604872355 @default.
• W1778048163 hasRelatedWork W2748952813 @default.
• W1778048163 hasRelatedWork W2899084033 @default.
• W1778048163 hasRelatedWork W3032375762 @default.
• W1778048163 hasRelatedWork W3108674512 @default.
• W1778048163 hasVolume "6" @default.
• W1778048163 isParatext "false" @default.
• W1778048163 isRetracted "false" @default.
• W1778048163 magId "1778048163" @default.
• W1778048163 workType "article" @default.