241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
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336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
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299 KEGG pathways;
876 Reactome pathways;
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last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
Protein kinase C delta type;2.7.11.13;Tyrosine-protein kinase PRKCD;2.7.10.2;nPKC-delta;Protein kinase C delta type regulatory subunit;Protein kinase C delta type catalytic subunit;Sphingosine-dependent protein kinase-1;SDK1;
Protein Family
Belongs to the protein kinase superfamily AGC Ser/Thrprotein kinase family PKC subfamily
Cytoplasm Cytoplasm, perinuclear region Nucleus Cell membrane
Function (UniProt annotation)
Calcium-independent, phospholipid- and diacylglycerol(DAG)-dependent serine/threonine-protein kinase that playscontrasting roles in cell death and cell survival by functioningas a pro-apoptotic protein during DNA damage-induced apoptosis,but acting as an anti-apoptotic protein during cytokine receptor-initiated cell death, is involved in tumor suppression as well assurvival of several cancers, is required for oxygen radicalproduction by NADPH oxidase and acts as positive or negativeregulator in platelet functional responses Negatively regulates Bcell proliferation and also has an important function in self-antigen induced B cell tolerance induction Upon DNA damage,activates the promoter of the death-promoting transcription factorBCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcriptionand apoptosis In response to oxidative stress, interact with andactivate CHUK/IKKA in the nucleus, causing the phosphorylation ofp53/TP53 In the case of ER stress or DNA damage-inducedapoptosis, can form a complex with the tyrosine-protein kinaseABL1 which trigger apoptosis independently of p53/TP53 In cytosolcan trigger apoptosis by activating MAPK11 or MAPK14, inhibitingAKT1 and decreasing the level of X-linked inhibitor of apoptosisprotein (XIAP), whereas in nucleus induces apoptosis via theactivation of MAPK8 or MAPK9 Upon ionizing radiation treatment,is required for the activation of the apoptosis regulators BAX andBAK, which trigger the mitochondrial cell death pathway Canphosphorylate MCL1 and target it for degradation which issufficient to trigger for BAX activation and apoptosis Isrequired for the control of cell cycle progression both at G1/Sand G2/M phases Mediates phorbol 12-myristate 13-acetate (PMA)-induced inhibition of cell cycle progression at G1/S phase by up-regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclinCCNA2 promoter activity In response to UV irradiation canphosphorylate CDK1, which is important for the G2/M DNA damagecheckpoint activation Can protect glioma cells from the apoptosisinduced by TNFSF10/TRAIL, probably by inducing increasedphosphorylation and subsequent activation of AKT1 Is highlyexpressed in a number of cancer cells and promotes cell survivaland resistance against chemotherapeutic drugs by inducing cyclinD1 (CCND1) and hyperphosphorylation of RB1, and via several pro-survival pathways, including NF-kappa-B, AKT1 and MAPK1/3(ERK1/2) Can also act as tumor suppressor upon mitogenicstimulation with PMA or TPA In N-formyl-methionyl-leucyl-phenylalanine (fMLP)-treated cells, is required for NCF1 (p47-phox) phosphorylation and activation of NADPH oxidase activity,and regulates TNF-elicited superoxide anion production inneutrophils, by direct phosphorylation and activation of NCF1 orindirectly through MAPK1/3 (ERK1/2) signaling pathways May alsoplay a role in the regulation of NADPH oxidase activity ineosinophil after stimulation with IL5, leukotriene B4 or PMA Incollagen-induced platelet aggregation, acts a negative regulatorof filopodia formation and actin polymerization by interactingwith and negatively regulating VASP phosphorylation Downstream ofPAR1, PAR4 and CD36/GP4 receptors, regulates differentiallyplatelet dense granule secretion; acts as a positive regulator inPAR-mediated granule secretion, whereas it negatively regulatesCD36/GP4-mediated granule release Phosphorylates MUC1 in the C-terminal and regulates the interaction between MUC1 and beta-catenin The catalytic subunit phosphorylates 14-3-3 proteins(YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion (Bysimilarity) Phosphorylates ELAVL1 in response to angiotensin-2treatment (PubMed:18285462)
Catalytic Activity (UniProt annotation)
ATP + a protein = ADP + a phosphoprotein ATP + a [protein]-L-tyrosine = ADP + a[protein]-L-tyrosine phosphate
Inflammatory immune response requires the recruitment of leukocytes to the site of inflammation upon foreign insult. Chemokines are small chemoattractant peptides that provide directional cues for the cell trafficking and thus are vital for protective host response. In addition, chemokines regulate plethora of biological processes of hematopoietic cells to lead cellular activation, differentiation and survival.The chemokine signal is transduced by chemokine receptors (G-protein coupled receptors) expressed on the immune cells. After receptor activation, the alpha- and beta-gamma-subunits of G protein dissociate to activate diverse downstream pathways resulting in cellular polarization and actin reorganization. Various members of small GTPases are involved in this process. Induction of nitric oxide and production of reactive oxygen species are as well regulated by chemokine signal via calcium mobilization and diacylglycerol production.
Autophagy (or macroautophagy) is a cellular catabolic pathway involving in protein degradation, organelle turnover, and non-selective breakdown of cytoplasmic components, which is evolutionarily conserved among eukaryotes and exquisitely regulated. This progress initiates with production of the autophagosome, a double-membrane intracellular structure of reticular origin that engulfs cytoplasmic contents and ultimately fuses with lysosomes for cargo degradation. Autophagy is regulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation and ER stress. Constitutive level of autophagy plays an important role in cellular homeostasis and maintains quality control of essential cellular components.
The vascular smooth muscle cell (VSMC) is a highly specialized cell whose principal function is contraction. On contraction, VSMCs shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure. The principal mechanisms that regulate the contractile state of VSMCs are changes in cytosolic Ca2+ concentration ([Ca2+]c). In response to vasoconstrictor stimuli, Ca2+ is mobilized from intracellular stores and/or the extracellular space to increase [Ca2+]c in VSMCs. The increase in [Ca2+]c, in turn, activates the Ca2+-CaM-MLCK pathway and stimulates MLC20 phosphorylation, leading to myosin-actin interactions and, hence, the development of contractile force. The sensitivity of contractile myofilaments or MLC20 phosphorylation to Ca2+ can be secondarily modulated by other signaling pathways. During receptor stimulation, the contractile force is greatly enhanced by the inhibition of myosin phosphatase. Rho/Rho kinase, PKC, and arachidonic acid have been proposed to play a pivotal role in this enhancement. The signaling events that mediate relaxation include the removal of a contractile agonist (passive relaxation) and activation of cyclic nucleotide-dependent signaling pathways in the continued presence of a contractile agonist (active relaxation). Active relaxation occurs through the inhibition of both Ca2+ mobilization and myofilament Ca2+ sensitivity in VSMCs.
Specific families of pattern recognition receptors are responsible for detecting various pathogens and generating innate immune responses. The intracellular NOD-like receptor (NLR) family contains more than 20 members in mammals and plays a pivotal role in the recognition of intracellular ligands. NOD1 and NOD2, two prototypic NLRs, sense the cytosolic presence of the bacterial peptidoglycan fragments that escaped from endosomal compartments, driving the activation of NF-{kappa}B and MAPK, cytokine production and apoptosis. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of multiprotein complexes called inflammasomes. The activated of caspase-1 regulates maturation of the pro-inflammatory cytokines IL-1B, IL-18 and drives pyroptosis.
C-type lectin receptors (CLRs) are a large superfamily of proteins characterized by the presence of one or more C-type lectin-like domains (CTLDs). CLRs function as pattern-recognition receptors (PRRs) for pathogen-derived ligands in dendric cells, macrophages, neutrophils, etc., such as Dectin-1 and Dectin-2 for recognition of fungi-derived B-glucan and high mannose-type carbohydrates. Upon ligand binding, CLRs stimulate intracellular signaling cascades that induce the production of inflammatory cytokines and chemokines, consequently triggering innate and adaptive immunity to pathogens.
Phagocytosis plays an essential role in host-defense mechanisms through the uptake and destruction of infectious pathogens. Specialized cell types including macrophages, neutrophils, and monocytes take part in this process in higher organisms. After opsonization with antibodies (IgG), foreign extracellular materials are recognized by Fc gamma receptors. Cross-linking of Fc gamma receptors initiates a variety of signals mediated by tyrosine phosphorylation of multiple proteins, which lead through the actin cytoskeleton rearrangements and membrane remodeling to the formation of phagosomes. Nascent phagosomes undergo a process of maturation that involves fusion with lysosomes. The acquisition of lysosomal proteases and release of reactive oxygen species are crucial for digestion of engulfed materials in phagosomes.
Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory.
The TRP channels that exhibit a unique response to temperature have been given the name thermo-TRPs. Among all thermo- TRP channels, TRPV1-4, TRPM8, and TRPA1 are expressed in subsets of nociceptive dorsal root ganglion (DRG) neuron cell bodies including their peripheral and central projections. These channels can be modulated indirectly by inflammatory mediators such as PGE2, bradykinin, ATP, NGF, and proinflammatory cytokines that are generated during tissue injury. While the noxious heat receptor TRPV1 is sensitized (that is, their excitability can be increased) by post-translational modifications upon activation of G-protein coupled receptors (GPCRs) or tyrosine kinase receptors, the receptors for inflammatory mediators, the same action appears to mainly desensitize TRPM8, the main somatic innocuous cold sensor. This aforementioned sensitization could allow the receptor to become active at body temperature, so it not only contributes toward thermal hypersensitivity but also is possibly a substrate for ongoing persistent pain.
Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnRHR is coupled to Gq/11 proteins to activate phospholipase C which transmits its signal to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates the intracellular protein kinase C (PKC) pathway and IP3 stimulates release of intracellular calcium. In addition to the classical Gq/11, coupling of Gs is occasionally observed in a cell-specific fashion. Signaling downstream of protein kinase C (PKC) leads to transactivation of the epidermal growth factor (EGF) receptor and activation of mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPK. Active MAPKs translocate to the nucleus, resulting in activation of transcription factors and rapid induction of early genes.
Estrogens are steroid hormones that regulate a plethora of physiological processes in mammals, including reproduction, cardiovascular protection, bone integrity, cellular homeostasis, and behavior. Estrogen mediates its cellular actions through two signaling pathways classified as nuclear-initiated steroid signalingand membrane-initiated steroid signaling. In the nuclearpathway, estrogen binds either ERalpha or ERbeta, which in turn translocates to the nucleus, binds DNA at ERE elements and activates the expression of ERE-dependent genes. In membranepathway, Estrogen can exert its actions through a subpopulation of ER at the plasma membrane (mER) or novel G-protein coupled E2 receptors (GPER). Upon activation of these receptors various signaling pathways (i.e. Ca2+, cAMP, protein kinase cascades) are rapidly activated and ultimately influence downstream transcription factors.
Insulin resistance is strongly associated with type II diabetes. Diabetogenicfactors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process.The development of type II diabetes requires impaired beta-cell function. Chronic hyperglycemia has been shown to induce multiple defects in beta-cells. Hyperglycemia has been proposed to lead to large amounts of reactive oxygen species (ROS) in beta-cells, with subsequent damage to cellular components including PDX-1. Loss of PDX-1, a critical regulator of insulin promoter activity, has also been proposed as an important mechanism leading to beta-cell dysfunction.Although there is little doubt as to the importance of genetic factors in type II diabetes, genetic analysis is difficult due to complex interaction among multiple susceptibility genes and between genetic and environmental factors. Genetic studies have therefore given very diverse results. Kir6.2 and IRS are two of the candidate genes. It is known that Kir6.2 and IRS play central roles in insulin secretion and insulin signal transmission, respectively.
Insulin resistance is a condition where cells become resistant to the effects of insulin. It is often found in people with health disorders, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular diseases. In this diagram multiple mechanisms underlying insulin resistance are shown: (a) increased phosphorylation of IRS (insulin receptor substrate) protein through serine/threonine kinases, such as JNK1 and IKKB, and protein kinase C, (b) increased IRS-1 proteasome degradation via mTOR signaling pathway, (c) decreased activation of signaling molecules including PI3K and AKT, (d) increase in activity of phosphatases including PTPs, PTEN, and PP2A. Regulatory actions such as oxidative stress, mitochondrial dysfunction, accumulation of intracellular lipid derivatives (diacylglycrol and ceramides), and inflammation (via IL-6 and TNFA) contribute to these mechanisms. Consequently, insulin resistance causes reduced GLUT4 translocation, resulting in glucose takeup and glycogen synthesis in skeletal muscle as well as increased hepatic gluconeogenesis and decreased glycogen synthesis in liver. At the bottom of the diagram, interplay between O-GlcNAcylation and serine/threonine phosphorylation is shown. Studies suggested that elevated O-GlcNAc level was correlated to high glucose-induced insulin resistance. Donor UDP-GlcNAc is induced through hexosamine biosynthesis pathway and added to proteins by O-GlcNAc transferase. Elevation of O-GlcNAc modification alters phosphorylation and function of key insulin signaling proteins including IRS-1, PI3K, PDK1, Akt and other transcription factor and cofactors, resulting in the attenuation of insulin signaling cascade.
Advanced glycation end products (AGEs) are a complex group of compounds produced through the non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids, primarily due to aging and under certain pathologic condition such as huperglycemia. Some of the best chemically characterized AGEs include N-epsilon-carboxy-methyl-lysine (CML), N-epsilon-carboxy-ethyl-lysine (CEL), and Imidazolone. The major receptor for AGEs, known as receptor for advanced glycation end products (RAGE or AGER), belongs to the immunoglobulin superfamily and has been described as a pattern recognition receptor. AGE/RAGE signaling elicits activation of multiple intracellular signal pathways involving NADPH oxidase, protein kinase C, and MAPKs, then resulting in NF-kappaB activity. NF-kappa B promotes the expression of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha and a variety of atherosclerosis-related genes, including VCAM-1, tissue factor, VEGF, and RAGE. In addition, JAK-STAT-mediated and PI3K-Akt-dependent pathways are induced via RAGE, which in turn participate in cell proliferation and apoptosis respectively. Hypoxia-mediated induction of Egr-1 was also shown to require the AGE-RAGE interaction. The results of these signal transductions have been reported to be the possible mechanism that initates diabetic complications.
Apoptotic cell death is achieved by the caspase-mediated\rcleavage of various vital proteins. Among caspase targets are proteins such as E-cadherin, Beta-catenin, alpha fodrin, GAS2, FADK, alpha adducin, HIP-55, and desmoglein involved in cell adhesion and maintenance of the cytoskeletal architecture. Cleavage of proteins such as APC and CIAP1 can further stimulate apoptosis by produce proapoptotic proteins (reviewed in Fischer et al., 2003. See also Wee et al., 2006 and the CASVM Caspase Substrates Database: http://www.casbase.org/casvm/squery/index.html )
One important physiological role for Calmodulin is the regulation of adenylylcyclases. Four of the nine known adenylylcyclases are calcium sensitive, in particular type 8 (AC8)
Hydrolysis of phosphatidyl inositol-bisphosphate (PIP2) by phospholipase C (PLC) produces diacylglycerol (DAG) and inositol triphosphate (IP3). Both are potent second messengers. IP3 diffuses into the cytosol, but as DAG is a hydrophobic lipid it remains within the plasma membrane. IP3 stimulates the release of calcium ions from the smooth endoplasmic reticulum, while DAG activates the conventional and unconventional protein kinase C (PKC) isoforms, facilitating the translocation of PKC from the cytosol to the plasma membrane. The effects of DAG are mimicked by tumor-promoting phorbol esters. DAG is also a precursor for the biosynthesis of prostaglandins, the endocannabinoid 2-arachidonoylglycerol and an activator of a subfamily of TRP-C (Transient Receptor Potential Canonical) cation channels 3, 6, and 7
All ERBB2 heterodimers, ERBB2:EGFR, ERBB2:ERBB3 and ERBB2:ERBB4, are able to activate RAF/MAP kinase cascade by recruiting SHC1 (Pinkas-Kramarski et al. 1996, Sepp-Lorenzino et al. 1996) to phosphorylated C-tail tyrosine residues in either EGFR (Y1148 and Y1173), ERBB2 (Y1196, Y1221, Y1222 and Y1248), ERBB3 (Y1328) or ERBB4 (Y1188 and Y1242 in JM-A CYT1 isoform, Y1178 and Y1232 in JM-B CYT1 isoform, Y1172 and Y1226 in JM-A CYT2 isoform). SHC1 recruitment is followed by phosphorylation (Segatto et al. 1993, Soler et al. 1994), and the phosphorylated SHC1 recruits GRB2:SOS1 complex (Xie et al. 1995), which leads to SOS1-mediated guanyl-nucleotide exchange on RAS (Xie et al. 1995) and downstream activation of RAF and MAP kinases
Phospholipases play an integral role in phagocytosis by generating essential second messengers. An early step in phagocytic signaling is the association of PIP2 and IP3 with the phagocytic cup. These are formed by the activity of phosphoinositol kinases and phospholipases. PI3K is has been shown to accumulate at phagocytic cups and converts PI (4,5)P2 to PI (3,4,5)P3. These phosphoinositides are capable of binding and increasing the activity of proteins that regulate the actin cytoskeleton. Phospholipases are lipid modifying enzymes that produce lipid mediators such as diacylglycerol (DAG), arachidonic acid (AA) and IP3. Phopsholipases PLA, PLC and PLD have been shown to be involved in antibody (IgG) mediated phagocytosis. The PLC product IP3 stimulates release of calcium from the endoplasmic reticulum. This Ca+2 concentration increase is greatest in the cytoplasm surrounding the phagocytic cup. Calcium is involved in the various stages of phagosome formation, including phagocytic ingestion and phagosome maturation
The heterotrimeric G protein G alpha (z), is a member of the G (i) family. Unlike other G alpha (i) family members it lacks an ADP ribosylation site cysteine four residues from the carboxyl terminus and is thus pertussis toxin-insensitive. It inhibits adenylyl cyclase types I, V and VI (Wong Y H et al. 1992). G alpha (z) interacts with the Rap1 GTPase activating protein (Rap1GAP) to attenuate Rap1 signaling. Like all G-proteins G alpha (z) has an intrinsic GTPase activity, but this activity tends to be lower for the pertussis toxin insensitive G-proteins, most strikingly so for G alpha (z), whose kcat value for GTP hydrolysis is 200-fold lower than those of G alpha (s) or G alpha (i) (Grazziano et al. 1989). G alpha (z) knockout mice have disrupted platelet aggregation at physiological concentrations of epinephrine and responses to several neuroactive drugs are altered (Yang et al. 2000). Regulator of G-protein Signalling (RGS) proteins can regulate the activity of G alpha (z) (Soundararajan M et al. 2008)
HuR (ELAVL1) is a ubiquitous protein that binds AU-rich elements in mRNAs and acts to stabilize the mRNAs. HuR activity is controlled by phosphorylation, with PKC alpha and PCK delta enhancing the ability of HuR to bind and stabilize mRNAs. Binding of mRNAs occurs in the nucleus and HuR then interacts with the CRM1 export pathway to transfer the mRNA to the cytoplasm. The mechanism by which HuR shields the mRNA from degradation is unknown.HuR also regulates translation of some mRNAs, in some cases repressing translation and in some cases enhancing translation of bound mRNAs by recruiting them to polysomes.HuR binds and regulates mRNAs encoding Cyclooxygenase-2 (COX2, PTGS2), Cyclin A (CCNA, CCNA2), Cyclin D1 (CCND1), Cyclin B1 (CCNB1), CD83 antigen (CD83), and proto-oncogene c-Fos (FOS).HuR is a member of a family of proteins that also contains HuD (ELAVL4), HuB (ELAVL2), and HuC (ELAVL3). HuB, HuC, and HuD are specifically expressed in neural tissue.HuR participates in apoptosis. During lethal stress HuR becomes mostly cytoplasmic and is a target of Caspase-3 and Caspase-7. The cleavage products of HuR in turn promote apoptosis
VEGFR2 stimulates ERK not via GRB2-SOS-RAS, but via pY1175-dependent phosphorylation of PLC gamma and subsequent activation of PKCs. PKC plays an important mediatory role in the proliferative Ras/Raf/MEK/ERK pathway. PKC alpha can intersect the Ras/Raf/MEK/ERK cascade at the level of Ras (Clark et al. 2004) or downstream of Ras through direct phosphorylation of Raf (Kolch et al. 1993). VEGF stimulation leads to Ras activation in a Ras-guanine nucleotide exchange factor (GEF) independent mechanism. It rather relies on modulating the regulation of Ras-GTPase activating protein (GAP) than regulation of Ras-GEFS (Wu et al. 2003)
CLEC7A (also known as Dectin-1) is a pattern-recognition receptor (PRR) expressed by myeloid cells (macrophages, dendritic cells and neutrophils) that detects pathogens by binding to beta-1,3-glucans in fungal cell walls and triggers direct innate immune responses to fungal and bacterial infections. CLEC7A belongs to thetype-II C-type lectin receptor (CLR) family that can mediate its own intracellular signaling. Upon binding particulate beta-1,3-glucans, CLEC7A mediates intracellular signalling through its cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)-like motif (Brown 2006). CLEC7A signaling can induce the production of various cytokines and chemokines, including tumour-necrosis factor (TNF), CXC-chemokine ligand 2 (CXCL2, also known as MIP2), interleukin-1beta (IL-1b), IL-2, IL-10 and IL-12 (Brown et al. 2003), it also triggers phagocytosis and stimulates the production of reactive oxygen species (ROS), thus contributing to microbial killing (Gantner et al. 2003, Herre et al. 2004, Underhill et al. 2005, Goodridge at al. 2011, Reid et al. 2009). These cellular responses mediated by CLEC7A rely on both Syk-dependent and Syk-independent signaling cascades. The pathways leading to the Syk-dependent activation of NF-kB can be categorised into both canonical and non-canonical routes (Gringhuis et al. 2009). Activation of the canonical NF-kB pathway is essential for innate immunity, whereas activation of the non-canonical pathway is involved in lymphoid organ development and adaptive immunity (Plato et al. 2013)
Neutrophils are the most abundant leukocytes (white blood cells), indispensable in defending the body against invading microorganisms. In response to infection, neutrophils leave the circulation and migrate towards the inflammatory focus. They contain several subsets of granules that are mobilized to fuse with the cell membrane or phagosomal membrane, resulting in the exocytosis or exposure of membrane proteins. Traditionally, neutrophil granule constituents are described as antimicrobial or proteolytic, but granules also introduce membrane proteins to the cell surface, changing how the neutrophil responds to its environment (Borregaard et al. 2007). Primed neutrophils actively secrete cytokines and other inflammatory mediators and can present antigens via MHC II, stimulating T-cells (Wright et al. 2010).Granules form during neutrophil differentiation. Granule subtypes can be distinguished by their content but overlap in structure and composition. The differences are believed to be a consequence of changing protein expression and differential timing of granule formation during the terminal processes of neutrophil differentiation, rather than sorting (Le Cabec et al. 1996). The classical granule subsets are Azurophil or primary granules (AG), secondary granules (SG) and gelatinase granules (GG). Neutrophils also contain exocytosable storage cell organelles, storage vesicles (SV), formed by endocytosis they contain many cell-surface markers and extracellular, plasma proteins (Borregaard et al. 1992). Ficolin-1-rich granules (FG) are like GGs highly exocytosable but gelatinase-poor (Rorvig et al. 2009)
Interferon-gamma (IFN-gamma) belongs to the type II interferon family and is secreted by activated immune cells-primarily T and NK cells, but also B-cells and APC. INFG exerts its effect on cells by interacting with the specific IFN-gamma receptor (IFNGR). IFNGR consists of two chains, namely IFNGR1 (also known as the IFNGR alpha chain) and IFNGR2 (also known as the IFNGR beta chain). IFNGR1 is the ligand binding receptor and is required but not sufficient for signal transduction, whereas IFNGR2 do not bind IFNG independently but mainly plays a role in IFNG signaling and is generally the limiting factor in IFNG responsiveness. Both IFNGR chains lack intrinsic kinase/phosphatase activity and thus rely on other signaling proteins like Janus-activated kinase 1 (JAK1), JAK2 and Signal transducer and activator of transcription 1 (STAT-1) for signal transduction. IFNGR complex in its resting state is a preformed tetramer and upon IFNG association undergoes a conformational change. This conformational change induces the phosphorylation and activation of JAK1, JAK2, and STAT1 which in turn induces genes containing the gamma-interferon activation sequence (GAS) in the promoter
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