The transcription factor activator protein (AP)-1 consists of Jun (c-Jun, JunB, and JunD), Fos (c-Fos, FosB, Fra1, and Fra2), ATF (ATFa, ATF-2 and ATF-3) and JDP (JDP-1 and JDP-2) family members []. They are basic leucine zipper transcription factors that play a central role in regulating gene transcription in various biological processes []. This entry includes Jun family members. AP-1 proteins have a α-helical bZIP domain, which contains a basic DNA-binding region and regularly spaced leucine residues known as the leucine zipper motif []. They have similar protein structure and can either form homodimers or form heterodimers with other AP-1 proteins (predominantly with Jun proteins), which can then bind to TRE-like sequences (consensus sequence 5'-TGAG/CTCA-3') []. Each of these proteins are expressed in different tissues and can be regulated in different ways, which means that every cell type has a complex mixture of AP-1 dimers with subtly different functions [].
Jun dimerization protein 2 (JDP2) regulates the AP-1-mediated activation of transcription []. It can either form homodimers or form heterodimers with other AP-1 members, such as c-Jun, JunB, JunD, and ATF-2 []. It binds directly to histones and DNAs and then inhibits the p300-mediated acetylation both of core histones and of reconstituted nucleosomes that contain JDP2 recognition DNA sequences []. JDP2 plays important roles in cellular differentiation, ageing and cancer [, ].
Transcription factor activator protein (AP)-1, comprising Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra1, and Fra2) family members, plays a central role in regulating gene transcription in various biological processes []. Fos protein family members form stable heterodimerswith Jun proteins and thereby enhance their DNA-bindingactivity []. This entry reprsents FosB []. FosB-null mice display impaired adult hippocampal neurogenesis and spontaneous epilepsy with depressive behavior [].
Basic leucine zipper transcriptional factor ATF-like 3 (B-ATF-3, also known as p21SNFT) is a AP-1 family transcription factor that can replace Fos in dimerisation with Jun on a consensus AP-1 binding site (12-O-tetradecanolyphorbol-13-acetate response element (TRE)) and interact with Jun and NF-AT at the distal NF-AT/AP-1 enhancer element []. It may repress transcriptional activity by inducing a unique conformation in the transcription factor complex [, ]. It controls the differentiation of CD8+ thymic conventional dendritic cells in the immune system [].
Transcription factor activator protein (AP)-1, comprising Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra1, and Fra2) family members, plays a central role in regulating gene transcription in various biological processes []. Fos protein family members are involved in rodent fibroblasts transformation []. Fos protein family members form stable heterodimers with Jun proteins and thereby enhance their DNA-bindingactivity [].This entry represents fos-related antigen 1 (Fra1). It is an activator of bone matrix formation []and can negatively regulate pulmonary fibrosis in vivo []. It is overexpressed in breast cancer cells and may be a possible biomarker for prognosis of breast cancer [].
JAMP is a Jun N-terminal kinase 1 (JNK1)-associated membrane protein. It associates with JNK1 through its C-terminal domain and regulates the duration of JNK1 activity in response to diverse stress stimuli []. It is an important component for coordinated clearance of misfolded proteins from the ER [, ].
Transcription factor JunB is a member of the transcription factor activator protein (AP)-1 family, comprising Jun (c-Jun, JunB, and JunD), Fos (c-Fos, FosB, Fra1, and Fra2), ATF (ATFa, ATF-2 and ATF-3) and JDP (JDP-1 and JDP-2) family members []. They are basic leucine zipper transcription factors that play a central role in regulating gene transcription in various biological processes []. JunB may serve as a biomarkers for prognosis of breast cancer [].AP-1 proteins have a α-helical bZIP domain, which contains a basic DNA-binding region and regularly spaced leucine residues known as the leucine zipper motif []. They have similar protein structure and can either form homodimers or form heterodimers with other AP-1 proteins (predominantly with Jun proteins), which can then bind to TRE-like sequences (consensus sequence 5'-TGAG/CTCA-3') []. Each of these proteins are expressed in different tissues and can be regulated in different ways, which means that every cell type has a complex mixture of AP-1 dimers with subtly different functions [].
The transcription factor activator protein (AP)-1 consists of Jun (c-Jun, JunB, and JunD), Fos (c-Fos, FosB, Fra1, and Fra2), ATF and JDP family members []. They are basic leucine zipper transcription factors that play a central role in regulating gene transcription in various biological processes []. This entry includes Fos, ATF-3 and JDP family members. AP-1 proteins have a α-helical bZIP domain, which contains a basic DNA-binding region and regularly spaced leucine residues known as the leucine zipper motif []. They have similar protein structure and can either form homodimers or form heterodimers with other AP-1 proteins (predominantly with Jun proteins), which can then bind to TRE-like sequences (consensus sequence 5'-TGAG/CTCA-3') []. Each of these proteins are expressed in different tissues and can be regulated in different ways, which means that every cell type has a complex mixture of AP-1 dimers with subtly different functions [].
Transcription factor activator protein (AP)-1, comprising Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra1, and Fra2) family members, plays a central role in regulating gene transcription in various biological processes []. Fos protein family members form stable heterodimerswith Jun proteins and thereby enhance their DNAbindingactivity []. This entry reprsents fos-related antigen 2 (Fra2), which is implicated in TGFbeta signalling. Fra2 is a positive regulator of bone and matrix formation in mice and humans []. Fra2 is a STAT5 (signal transducers and activators of transcription 5) target gene regulated by IL-2 in human CD4 T cells []. It may also play an important role in the pathogenesis of systemic sclerosis, an autoimmune disease of unknown etiology that affects the skin and a variety of internal organs including the lungs, heart, and gastrointestinal tract [].
Transcription factor activator protein (AP)-1, comprising Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra1, and Fra2) family members, plays a central role in regulating gene transcription in various biological processes []. Fos protein family members are involved in rodent fibroblasts transformation []. Fos protein family members form stable heterodimers with Jun proteins and thereby enhance their DNA-bindingactivity [].This entry represents the c-Fos and v-Fos proteins. c-Fos is the human homologue of the retroviral oncogene v-Fos. c-Fos can regulate growth not only by its transcription-factor activity, but also through mechanisms independent of its genomic AP-1 activity. By association with particular enzymes, it can act as a cytoplasmic activator of the biosynthesis of lipids both in normal and pathological cellular processes []. In the nucleus, where lipid synthesis also occurs, it binds to PI4P5K (phosphatidylinositol-4-monophosphate 5-kinase) and activates nuclear PtdIns(4,5)P2 synthesis in response to growth signals, which, in turn, promotes transcriptional changes [].
Transcription factor c-Jun (also known as transcription factor AP-1) is a member of the transcription factor activator protein (AP)-1 family, comprising Jun (c-Jun, JunB, and JunD), Fos (c-Fos, FosB, Fra1, and Fra2), ATF (ATFa, ATF-2 and ATF-3) and JDP (JDP-1 and JDP-2) family members []. They are basic leucine zipper transcription factors that play a central role in regulating gene transcription in various biological processes []. c-Jun was originally identified as the normal cellular counterpart of the viral Jun oncoprotein (v-Jun) encoded by an avian sarcoma virus (ASV17). The 39kDa c-Jun protein consists of a C-terminal basic region-leucine zipper (B-ZIP) DNA-binding domain and a N-terminal transcriptional activation domain.AP-1 proteins have a α-helical bZIP domain, which contains a basic DNA-binding region and regularly spaced leucine residues known as the leucine zipper motif []. They have similar protein structure and can either form homodimers or form heterodimers with other AP-1 proteins (predominantly with Jun proteins), which can then bind to TRE-like sequences (consensus sequence 5'-TGAG/CTCA-3') []. Each of these proteins are expressed in different tissues and can be regulated in different ways, which means that every cell type has a complex mixture of AP-1 dimers with subtly different functions [].
Activating transcription factor or cAMP-dependent transcription factor ATF-2, also known as CRE-BP1, regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response. ATF-2 needs to be phosphorylated by Jun N-terminal kinase (JNK), p38 (MAPK14), or extracellular-signal-regulated kinase 1 (ERK1) in order to be transcriptionally active. Activated ATF-2 then form dimers with proteins, such as members of the AP-1 family, and regulates gene transcription []. It has been implicated in several pathological conditions, including neurological diseases and cancer [, ].
Basic leucine zipper transcriptional factor ATF-like (BATF) is a transcription factor that dimerises with Jun class factors to bind AP-1 DNA sites []. It does not only inhibit AP-1-driven transcription, but also has positive transcriptional activities in dendritic cells, B cells and T cells through its interaction with members of the interferon-regulatory factor (IRF) family []. BATF controls the differentiation of lineage-specific cells in the immune system: specifically mediates the differentiation of T-helper 17 cells (Th17), follicular T-helper cells (TfH), CD8+ dendritic cells and class-switch recombination (CSR) in B-cells [].
Transcription factor JunD is a member of the transcription factor activator protein (AP)-1 family, comprising Jun (c-Jun, JunB, and JunD), Fos (c-Fos, FosB, Fra1, and Fra2), ATF (ATFa, ATF-2 and ATF-3) and JDP (JDP-1 and JDP-2) family members []. They are basic leucine zipper transcription factors that play a central role in regulating gene transcription in various biological processes []. This entry also includes transcription factor AP-1 (Jra) from Drosophila, which recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3' and has a role in dorsal closure [, , ].AP-1 proteins have a α-helical bZIP domain, which contains a basic DNA-binding region and regularly spaced leucine residues known as the leucine zipper motif []. They have similar protein structure and can either form homodimers or form heterodimers with other AP-1 proteins (predominantly with Jun proteins), which can then bind to TRE-like sequences (consensus sequence 5'-TGAG/CTCA-3') []. Each of these proteins are expressed in different tissues and can be regulated in different ways, which means that every cell type has a complex mixture of AP-1 dimers with subtly different functions [].
TNF receptor-associated factor 1 (TRAF1) plays a role in the regulation of cell survival and apoptosis []. TRAF1 is unique among TRAF proteins in that it lacks a RING domain found in the N-terminal regions of other TRAFs []. The heterotrimer formed by TRAF1 and TRAF2 is part of a E3 ubiquitin-protein ligase complex that promotes ubiquitination of target proteins, such as MAP3K14 [, ].TRAF1 is unique among the TRAFs in that it lacks a RING domain, which is critical for the activation of nuclear factor-kappaB and Jun NH2-terminal kinase. Studies on TRAF1-deficient mice suggest that TRAF1 has a negative regulatory role in TNFR-mediated signaling events []. TRAF1 contains one zinc finger and one TRAF domain.The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors [, ].
TNF receptor-associated factor 1 (TRAF1) plays a role in the regulation of cell survival and apoptosis []. TRAF1 is unique among TRAF proteins in that it lacks a RING domain found in the N-terminal regions of other TRAFs []. The heterotrimer formed by TRAF1 and TRAF2 is part of a E3 ubiquitin-protein ligase complex that promotes ubiquitination of target proteins, such as MAP3K14 [, ].TRAF1 is unique among the TRAFs in that it lacks a RING domain, which is critical for the activation of nuclear factor-kappaB and Jun NH2-terminal kinase. Studies on TRAF1-deficient mice suggest that TRAF1 has a negative regulatory role in TNFR-mediated signaling events []. TRAF1 contains one zinc finger and one TRAF domain.
This entry represents the non-structural protein NS6 (also known as ORF6, accessory protein 6, or X3 protein), which is highly conserved among SARS-related coronaviruses [](this is distinct from NSP6 which is encoded on the replicase polyprotein). NS6 is located in the endoplasmic reticulum []. It has been reported that NS6 can increase the cellular gene synthesis and it can also induce apoptosis through Jun N-terminal kinase and Caspase-3 mediated stress. This protein can modulate host antiviral responses by inhibiting synthesis and signalling of interferon-beta (IFN-beta) via two complementary pathways. One involves NS6 interaction with host N-Myc (and STAT) interactor (Nmi) protein inducing its degradation via ubiquitin proteasome pathway, suppressing Nmi enhanced IFN signalling. The other pathway suppresses the translocation of signal transducer and activator of transcription 1 (STAT1) and downstream IFN signalling [].This protein interacts with Rae1 and Nup98 to prevent both nuclear import and export, which renders host cells incapable of responding to SARS-CoV-2 infection [].
This conserved domain is found in Thyroid adenoma-associated protein (THADA) from animals and in the yeast homologue tRNA (cytidine(32)-2'-O)-methyltransferase non-catalytic subunit TRM732 [, , ]. Trm732 forms a complex with the methyltransferase Trm7 to 2'- O- methylate tRNA residue 32 (Nm32), being required for Trm7 methylation activity. In humans, mutations of the Trm7 homologue FTSJ1, which interacts with THADA, impair Nm32 modifications, associated with non-syndromic X-linked intellectual disability [, , ]. It has been suggested that these proteins may play a role in additional biological processes not related to translation. This domain contains a RRSAGLP conserved motif that is required for tRNA modification activity (Funk HM et.al., Preprint from bioRxiv, 03 Jun 2021 DOI: 10.1101/2021.06.03.446962) [, , ].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. Homologues for the GFRalpha-1 receptor subtype have been cloned from mammalian and avian tissue. The receptor is activated by GDNF [], although there is evidence it can also bind neurturin, the principal ligand for GFRalpha-2 [].Activation of GFRalpha-1 triggers its interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. Homologues for the GFRalpha-2 receptor subtype have been cloned from mammalian and avian tissue. The receptor is preferentially activated by neurturin, although there is evidence that GFRalpha-2 can also bindGDNF if pre-coupled to its effector molecule [].Activation of GFRalpha-2 triggers its interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-3 has been cloned from mammalian tissue []. It represents the least conserved member of the GFR family in terms of amino acid sequence, and is activated by artemin [].Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-1 and 2 are activated by GDNF and NTN respectively, although some degree of ligand promiscuity is thought to occur []. Homologues for these receptor subtypes have been cloned from mammalian and avian tissue. The principal ligand for GFRalpha-3 is artemin. This receptor subtype is currently described only in mammals []. GFRalpha-4 is activated by persephin and has so far only been found in chicken []. This entry is general for types 1 to 3.Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways [].
Glial cell line-derived neurotrophic factor (GDNF) and its related factorsneurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-1 and 2 are activated by GDNF and NTN respectively, although some degree of ligand promiscuity is thought to occur []. Homologues for these receptor subtypes have been cloned from mammalian and avian tissue. The principal ligand for GFRalpha-3 is artemin. This receptor subtype is currently described only in mammals []. GFRalpha-4 is activated by persephin and has so far only been found in chicken []. This entry is general for types 1 to 3.Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma)dependent pathways [].
Pectate lyase is an enzyme involved in the maceration and soft rotting of plant tissue. Pectate lyase is responsible for the eliminative cleavage of pectate, yielding oligosaccharides with 4-deoxy-alpha-D-mann-4-enuronosyl groups at their non-reducing ends. The protein is maximally expressed late in pollen development. It has been suggested that the pollen expression of pectate lyase genes might relate to a requirement for pectin degradation during pollen tube growth []. Some of the proteins in this family are allergens []. Allergies are hypersensitivity reactions of the immune system to specific substances called allergens (such as pollen, stings, drugs, or food) that, in most people, result in no symptoms. A nomenclature system has been established for antigens (allergens) that cause IgE-mediated atopic allergies in humans [WHO/IUIS Allergen Nomenclature Subcommittee King T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E., Thomas W. Bull. World Health Organ. 72:797-806(1994)]. This nomenclature system is defined by a designation that is composed of the first three letters of the genus; a space; the first letter of the species name; a space and an arabic number. In the event that two species names have identical designations, they are discriminated from one another by adding one or more letters (as necessary) to each species designation.The allergens in this family include allergens with the following designations: Amb a 1, Amb a 2, Amb a 3, Cha o 1, Cup a 1, Cry j 1, Jun a 1.Two of the major allergens in the pollen of short ragweed (Ambrosia artemisiifolia) are Amb aI and Amb aII. The primary structure of Amb aII has been deduced and has been shown to share ~65% sequence identity with the Amb alpha I multigene family of allergens []. Members of the Amb aI/aII family include Nicotiana tabacum (Common tobacco) pectate lyase, which is similar to the deduced amino acid sequences of two pollen-specific pectate lyase genes identified in Solanum lycopersicum (Tomato) (Lycopersicon esculentum) []; Cry jI, a major allergenic glycoprotein of Cryptomeria japonica (Japanese cedar) - the most common pollen allergen in Japan []; and P56 and P59, which share sequence similarity with pectate lyases of plant pathogenic bacteria [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Eukaryotic serine-threonine mitogen-activated protein (MAP) kinases are key regulators of cellular signal transduction systems and are conserved from Saccharomyces cerevisiae (Baker's yeast) to human beings. MAPK pathways are signalling cascades differentially regulated by growth factors, mitogens, hormones and stress which mediate cell growth, differentiation and survival. MAPK activity is regulated through a (usually) three-tiered cascade composed of a MAPK, a MAPK kinase (MAPKK, MEK) and a MAPK kinase kinase (MAPKK, MEKK). Substrates for the MAPKs include other kinases and transcription factors []. Mammals express at least four distinctly related groups of MAPKs, extracellularly-regulated kinases (ERKs), c-jun N-terminal kinases (JNKs), p38 proteins and ERK5. Plant MAPK pathways have attracted increasing interest,resulting in the isolation of a large number of different components of MAPK cascades. MAPKs play important roles in the signalling of most plant hormones and in developmental processes []. In the budding yeast S. cerevisiae, four separate but structurally related mitogen-activated protein kinase (MAPK)activation pathways are known, regulating mating, cell integrity and osmosity [].Enzymes in this family are characterised by two domains separated by a deep channel where potential substrates might bind. The N-terminal domain creates a binding pocket for the adenine ring of ATP, and the C-terminal domain contains the catalytic base, magnesium binding sites and phosphorylation lip []. Almost all MAPKs possess a conserved TXY motif in which both the threonine andtyrosine residues are phosphorylated during activation of the enzyme byupstream dual-specificity MAP kinase kinases (MAPKKs).This group represents a mitogen-activated protein kinase kinase kinase kinase, which may play a role in the response to environmental stress. It appears to act upstream of the JUN N-terminal pathway [].
