IUPHAR/BPS Guide to Pharmacology CITE
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Type II RTKs: Insulin receptor family in GtoPdb v.2025.3
Get PDFThe circulating peptide hormones insulin and the related insulin-like growth factors (IGF) activate Class II receptor tyrosine kinases [13], to evoke cellular responses, mediated through multiple intracellular adaptor proteins. Unlike other receptor tyrosine kinases, the functional receptor in the insulin receptor family is derived from a single gene product, cleaved post-translationally into two peptides, which then cross-link via disulphide bridges to form a heterotetramer. Intriguingly, the endogenous peptide ligands are formed in a parallel fashion with post-translational processing producing a heterodimer linked by disulphide bridges. Signalling through the receptors is mediated through a rapid autophosphorylation event at intracellular tyrosine residues, followed by recruitment of multiple adaptor proteins, notably IRS1 (P35568), IRS2 (Q9Y4H2), SHC1 (P29353), GRB2 (P62993) and SOS1 (Q07889).Serum levels of free IGFs are kept low by the action of IGF binding proteins (IGFBP1-5, P08833, P18065, P17936, P22692, P24593), which sequester the IGFs; overexpression of IGFBPs may induce apoptosis, while IGFBP levels are also altered in some cancers
Type XIII RTKs: Ephrin receptor family in GtoPdb v.2025.3
Get PDFEphrin receptors are a family of 15 RTKs - the largest family of RTKs - with two identified subfamilies (EphA and EphB), which have a role in the regulation of neuronal development, cell migration, patterning and angiogenesis. Their ligands are membrane-associated proteins, thought to be glycosylphosphatidylinositol-linked for EphA (ephrin-A1 , ephrin-A2, ephrin-A3, ephrin-A4 and ephrin-A5) and transmembrane proteins for Ephrin B (ENSFM00250000002014: ephrin-B1, ephrin-B2 and ephrin-B3). Ephrin-A3 and ephrin-B3 have also been shown to interact with heparan sulphate proteoglycans [22]
Type XVI RTKs: DDR (collagen receptor) family in GtoPdb v.2025.3
Get PDFThe discoidin domain receptors DDR1 and DDR2 are structurally related receptor tyrosine kinases that function as collagen receptors. The 28 different collagens form the most abundant protein family in man. Collagens are found in the extracellular matrix and are generally deposited there in the form of supramolecular assemblies arranged from triple-helical rope-like structural units. In man, the main collagens include COL1A1, COL2A1, COL3A1 and COL4A1
Ceramide turnover in GtoPdb v.2025.3
Get PDFCeramides are a family of sphingophospholipids synthesized in the endoplasmic reticulum, which mediate cell stress responses, including apoptosis, autophagy and senescence, Serine palmitoyltransferase generates 3-ketosphinganine, which is reduced to dihydrosphingosine. N-Acylation allows the formation of dihydroceramides, which are subsequently reduced to form ceramides. Once synthesized, ceramides are trafficked from the ER to the Golgi bound to the ceramide transfer protein, CERT (COL4A3BP, Q9Y5P4). Ceramide can be metabolized via multiple routes, ensuring tight regulation of its cellular levels. Addition of phosphocholine generates sphingomyelin while carbohydrate is added to form glucosyl- or galactosylceramides. Ceramidase re-forms sphingosine or sphinganine from ceramide or dihydroceramide. Phosphorylation of ceramide generates ceramide phosphate. The determination of accurate kinetic parameters for many of the enzymes in the sphingolipid metabolic pathway is complicated by the lipophilic nature of the substrates
Type XIV RTKs: RET in GtoPdb v.2025.3
Get PDFThe RET (REarranged during Transfection) receptor is a transmembrane tyrosine kinase enzyme enzyme. RET forms a complex with members of the GPI-linked GDNF family receptors (GFR) to respond to GDNF family ligands, including glial cell-derived neurotrophic factors including glial cell-derived neurotrophic factor GDNF (211 aa); neurturin (197 aa); artemin (237 aa) and persephin (156 aa). RET also forms a complex with GFRAL, which is activated by growth differentiation factor 15 (GDF15) [25, 35]. RET is involved in neural crest development. Loss of function mutations lead to Hirschprung\u27s disease, while gain of function mutations lead to multiple endocrine neoplasias type 2A and 2B. There are isoforms - RET51 and RET9 - with distinct signalling properties
E3 ubiquitin ligase components in GtoPdb v.2025.3
Get PDFUbiquitination (a.k.a. ubiquitylation) is a protein post-translational modification that typically requires the sequential action of three enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) [50]. Ubiquitination of proteins can target them for proteasomal degradation, or modulate cellular processes including cell cycle progression, transcriptional regulation, DNA repair and signal transduction. E3 ubiquitin ligases, of which there are >600 in humans, are a family of highly heterogeneous proteins and protein complexes that recruit ubiquitin-loaded E2 enzymes to mediate transfer of the ubiquitin molecule from the E2 to protein substrates. Target substrate specificity is determined by a substrate recognition subunit within the E3 complex. E3 ligases are being exploited as pharmacological targets to facilitate targeted protein degradation (TPD), as an alternative to small molecule inhibitors [5], through the development of proteolysis targeting chimeras (PROTACs) and molecular glues
SLC3 and SLC7 families of heteromeric amino acid transporters (HATs) in GtoPdb v.2025.3
Get PDFThe SLC3 and SLC7 families combine to generate functional transporters, where the subunit composition is a disulphide-linked combination of a heavy chain (SLC3 family) with a light chain (SLC7 family) [1]
Pattern recognition receptors in GtoPdb v.2025.3
Get PDFPattern Recognition Receptors (PRRs, [118]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [21]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1β cleavage and secretion, and others in the initiation of the type I interferon response. PRRs included in the Guide To PHARMACOLOGY are:Catalytic PRRs (see links below this overview)Toll-like receptors (TLRs)Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)RIG-I-like receptors (RLRs)Caspase 4 and caspase 5 Non-catalytic PRRsAbsent in melanoma (AIM)-like receptors (ALRs)C-type lectin-like receptors (CLRs)Other pattern recognition receptorsAdvanced glycosylation end-product specific receptor (RAGE
Type III receptor serine/threonine kinases in GtoPdb v.2025.3
Get PDFType III serine/threonine kinase is often referred to as an accessory protein. While it has no known enzymatic activity, it can regulate the signalling of RSTKs [3, 2]
Formylpeptide receptors in GtoPdb v.2025.3
Get PDFThe human formylpeptide receptor subfamily of GPCRs (FPR: nomenclature described in [169, 227] [1, 2]) comprises three members (FPR1, FPR2, and FPR3). Two of these, FPR1 and FPR2, recognize peptides bearing N-terminal formyl-Met from invading bacteria [104] or mitochondria. These peptides function as danger signals in innate immunity. FPR1 and FPR2 are promiscuous and also recognize several non-formylated peptides, proteins, lipids and small molecules [169, 227, 104] of which some are able to initiate signals (balanced or biased) that mediate pro-inflammatory and/or inflammation resolving effects [136, 161]. In contrast, FPR3 remains less well-characterized in part due to the absence of selective ligands which has significantly impeded progress in its functional characterization [46, 173]