943 Risultati per: "AbFrontier"

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A growing body of evidence relates selenium to cancer prevention, immune system function, male fertility, cardiovascular disorder, control of the aging and neurodiseases process. Selenoproteins are thought to be responsible for the majority of these biomedical effects of selenium. Approximately 17 selenoproteins have been identified until now. Although the function of many selenoproteins are unknown, some play important roles in anti-oxidant mechanisms. It has been also implicated in the regulation of  signaling pathways through catalysis of thiol/ disulfide exchange.
Selenoprotein M(SelM) is especially expressed in a mammalian brain and is localized to the perinuclear structures (Golgi/ER). The roles of selM have not been clearly identified until present time.

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Enolase (2-phosphogly-cerate hydrolyase or phosphopyruvate hydrates) is a glycolytic enzyme that catalyzes the dehydration and conversion of 2-phosphoglycerate to phospho-enolpyruvate. It comprises three distint subunits, α, β and γ. The γγ and αγ dimeric forms of enolase, referred to as neuron-specific enolase(NSE), are localized mainly in neurons and neuroectodermal tissue. NSE has a high stability in biological fluids and can easily diffuse to the extracellular medium and cerebrospinal fluid(CSF) when neuronal membranes are injured. NSE is used clinically as a sensitive and useful marker of neuronal damage in several neurological disorders including stroke, hypoxic brain damage, status epilepticus, Creutzfeldt-Jakob disease, and herpetic encephalitis.

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Cathepsin D(CatD) is a ubiquitously expressed lysosomal aspartyl protease involved in the normal degradation of proteins apoptosis and autophagy. Human CatD is synthesized on the endoplasmic reticulum as a pre-pro-enzyme. Preprocathepsin D(412aa) is cleaved and glycosylated
to form an inactive procathepsin D (392aa) and then further cleaved to generate an active intermediate (348aa) single-chain molecule. The active intermediate is further processed into mature two chain form of cathepsin D, this processing step is carried out by cathepsin B or L. The two-chain form consists of an amino terminal light chain and a carboxyl-terminal heavy chain. Additionally, several more amino acids are removed from the carboxyl terminus of the heavy chain.
Procathepsin D (pCD), secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their proinvasive and pro-metastatic properties.

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Protein phosphatase-1(PP1) is one of the major Ser/Thr protein phosphatases and is ubiquitous in eukaryotic cells. PP1 is localized to its site of action by interacting with targeting or regulatory proteins, a majority of which contains a primary docking site referred to as the RVXF/W motif.
The catalytic subunit of PP1 exists as three isoforms, PP1a, PP1b, and PP1r. The PP1 catalytic subunits are small proteins of 37kDa, which are highly conserved, with their main differences falling in the C-term. The PP1 catalytic subunit exists in the cell in complex with a large number of targeting/regulatory subunits, thereby generating different enzyme forms that allow it to perform a diverse number of cellular functions.

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Receptor protein tyrosine phosphatase rho (RPTPρ/PTPRT) is a transmembrane protein that is highly expressed in the developing and adult central nervous system. It is a member of the RPTP R2B subfamily, which includes PTPκ, PTPμ and PCP-2. The R2B phosphatases are known to interact with members of the cadherin/catenin complex.
These four RPTPs share the same domain structure: an extracelluar domain, a juxtamembrane region, and two phosphatase domains. The extracellular domain of PTPR mediates cell-cell aggregation and that mutational inactivation of this phosphatase could promote tumor migration and metastasis. PTPRT is the most frequently mutated PTP in human cancers. STAT3 is a substrate of PTPRT. Phosphorylation of a tyrosine at 705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position.

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Lactoferrin(Lf), one of transferrin family, is found in external fluids, including milk and mucosal secretions, and prominent components of the secondary granules of neutrophils. Lf consists of a single polypeptide chain (approximately 80 kDa) folded into two structurally homologous lobes, each of which can reversibly bind one ferric ion (Fe3+). Lf plays a central role in iron metabolism and host defense system against microbial infection.

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The Cdc25 phosphatases are key regulators of normal cell division and the cell's response to DNA damage. Cdc25 isoforms are dual-specificity phosphatases that remove inhibitory phosphates from Thr14 and Tyr15 in Cdk1 and Cdk2. Cdk1 is necessary for mitotic onset and shares an overlapping role with Cdk2 in controlling S phase initiation. Cdc25 isoforms are also key targets of the Chk1 and Chk2 checkpoint kinases, which inactivate Cdc25 to halt cell cycle progression when DNA is damaged or incompletely replicated. Mammalian cells have three Cdc25 isoforms: Cdc25A, Cdc25B and Cdc25C. Cdc25A, which regulates both early and late cell-cycle transitions, controls progression through S phase and entry into mitosis, whereas Cdc25B and Cdc25C primarily control entry into mitosis.

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The members of the Src-family kinases are Src, Lyn, Fyn, Yes, Hck, Lck, Fgr, Blk, and Yrk. Each of these have a common structure consisting of an unique domain at the N-terminal, followed by SH3, SH2 and tyrosine kinase domains.
In immume cells, the Src-family kinases play roles as critical regulators of a large number of intracellular signaling pathways, including integrin signaling pathway. Integrins are major cellular receptor that mediate cell to cell and cell to substratum interactions.
The intracellular protein kinase Lyn participates both positively and negatively in B cell, mast cell, platelet and myeloid cell signaling. Lyn is the predominantly expressed Src-family kinase in B cells and its positive role is done through phosphorylation of the Igα and Igβ subunits of B cell receptor. Genetic deletion of Lyn results in autoimmunity, renal disease and premature mortality in mice, and generation of hyperactive Lyn results in the same phenotype, revealing the importance of the balance of Lyn signaling.

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Tau proteins are microtubule-associated proteins that are abundant in neurons in the central nervous system. In adult human brain, there are six tau isoforms that differ by the presence of either three or four C-terminal tandem repeated 31 or 33 amino acid sequences containing domains that are important for microtubule binding. Tau plays a crucial role in the neuron as it binds and stabilizes microtubules, and can regulate axonal transport; functions that are regulated by site-specific phosphorylation events. Abnormally hyperphosphorylated Tau protein, resulting in loss of function (the disruption of axonal transport) and gain of toxic function (formation of tau aggregates) at the same time, is deposited in cells as fibrillar lesions in numerous neurodegenerative diseases such as Alzheimer's disease, progressive supranuclear palsy, Pick's disease, corticobasal degeneration and post-encephalitic parkinsonism.

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Enolase (2-phosphogly-cerate hydrolyase or phosphopyruvate hydrates) is a glycolytic enzyme that catalyzes the dehydration and conversion of 2-phosphoglycerate to phospho-enolpyruvate. It comprises three distint subunits, alpha, beta and gamma. The gamma-gamma and alpha-gamma dimeric forms of enolase, referred to as neuron-specific enolase(NSE), are localized mainly in neurons and neuroectodermal tissue. NSE has a high stability in biological fluids and can easily diffuse to the extracellular medium and cerebrospinal fluid(CSF) when neuronal membranes are injured. NSE is used clinically as a sensitive and useful marker of neuronal damage in several neurological disorders including stroke, hypoxic brain damage, status epilepticus, Creutzfeldt-Jakob disease, and herpetic encephalitis.

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Methionine sulfoxide reductase B (MsrB), also known as SelX, is a selenoprotein. The oxidation of methionine at the sulfur atom leads to alternative epimers: R form of Met(O) and S form of Met(O). MsrB can reduce R form of both free and protein-incorporated methionine sulfoxide to methionine. It has a crucial role in protecting cells against oxidative damages.
MsrA reduces only the S epimer of Met(O), and MsrB reduces the R epimer of Met(O) in proteins. Although the catalytic mechanisms of MsrA and MsrB are similar, two Msrs have no sequence identity and no structural similarity.

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p53 is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. p53 has been described as "the guardian of the genome", referring to its role in conserving stability by preventing genome mutation. p53 has many anti-cancer mechanisms: activating DNA repair proteins when DNA has sustained damage, holding the cell cycle at the G1/S regulation point on DNA damage recognition, initiating apoptosis if the DNA damage proves to be irrepairable. Human p53 is 393 amino acids long and has three domains: N-terminal transcription-activation domain (TAD), which activates transcription factors. 2) central DNA-binding core domain (DBD) 3) C-terminal homo-oligomerisation domain (OD); tetramerization greatly increases the activity of p53 in vivo. Mutations that deactivate p53 in cancer usually occur in the DBD and most of these mutations destroy the ability of the protein to bind to its target DNA sequences.
The activity of p53 is regulated at different levels and includes control by multi-site phosphorylation. p53 is phosphorylated (Ser6 and Ser9) by casein kinase 1δ and casein kinase 1ε both in vitro and in vivo.

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Focal adhesion kinase subfamily consists of the non-receptor proline-rich protein tyrosine kinases (PTKs). Two members of the family are focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). These two kinases have molecular mass between 110-125 kDa and are closely related in their structure. The presence of two proline-rich motifs within the C-terminal domains is conserved.
Pyk2 is expressed primarily in brain and hematopoietic cells and becomes activated in response to stimulation through numerous receptors, including integrins, chemokine receptors, and antigen receptors. It is also expressed in both in bone-forming osteoblasts and bone-resorbing osteoclasts, and thought to have positive role in osteoblast maturation and bone resorption.Phosphorylation of Pyk2 leads to the recruitment of Src family kinases and the activation of Erks. Pyk2 also interacts with and phosphorylates the focal adhesion-related protein, paxillin, and other cytoskeletal proteins, suggesting its pivotal role in various cellular events.

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a catalytic enzyme commonly known to be involved in glycolysis. The enzyme exists as a tetramer of identical 37 kDa subunits. GAPDH catalyzes the reversible reduction of 1,3-bisphosphoglycerate to glyceraldehyde 3-phosphophate in the presence of NADPH. Apart from playing a key role in glycolysis, this ubiquitously expressed enzyme also displays other activities unrelated to its  glycolytic function. GAPDH is reported to be involved in the processes of DNA replication (1), DNA repair (2), nuclear RNA export (3-4), membrane fusion (5) and microtubule bundling. Other studies also provide evidence of GAPDH playing an essential part of the program of gene expression observed in apoptosis and as part of the cellular phenotype of age-related neurodegenerative diseases (6-7).

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The members of the Src-family kinases are Src, Lyn, Fyn, Yes, Hck, Lck, Fgr, Blk, and Yrk. Each of these have a common structure consisting of an unique domain at the N-terminal, followed by SH3, SH2 and tyrosine kinase domains.
In immume cells, the Src-family kinases play roles as critical regulators of a large number of intracellular signaling pathways, including integrin signaling pathway. Integrins are major cellular receptor that mediate cell to cell and cell to substratum interactions.
The intracellular protein kinase Lyn participates both positively and negatively in B cell, mast cell, platelet and myeloid cell signaling. Lyn is the predominantly expressed Src-family kinase in B cells and its positive role is done through phosphorylation of the Igα and Igβ subunits of B cell receptor. Genetic deletion of Lyn results in autoimmunity, renal disease and premature mortality in mice, and generation of hyperactive Lyn results in the same phenotype, revealing the importance of the balance of Lyn signaling.

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Peroxiredoxin (Prx) is a growing peroxidase family, whose mammalian members have been known to connect with cell proliferation, differentiation, and apoptosis. Many isoforms (about 50 proteins), collected in accordance to the amino acid sequence homology, particularly amino-terminal region containing active site cysteine residue, and the thiol-specific antioxidant activity, distribute throughout all the kingdoms. Among them, mammalian Prx consists of 6 different members grouped into typical 2-Cys, atypical 2-Cys Prx, and 1-Cys Prx. Except Prx VI belonging to 1- Cys Prx subgroup, the other five 2-Cys Prx isotypes have the thioredoxindependent peroxidase (TPx) activity utilizing thioredoxin, thioredoxin reductase, and NADPH as a reducing system. Mammalian Prxs are 20 – 30 kilodalton in molecular size and vary in subcellular localization: Prx I, II, and VI in cytosol, Prx III in mitochondria, Prx IV in ER and secretion, Prx V showing complicated distribution including peroxisome, mitochondria and cytosol.

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Green fluorescent protein (GFP) isolated from jellyfish Aequorea aequorea is a 238 amino acid protein with an apparent molecular weight of about 27-30 kDa on SDS-PAGE. Its chromophore is formed by cyclisation and oxidation of the three amino acids Ser65, Tyr66, and Gly67.
The numerous applications include : using GFP as a reporter for gene expression, as a marker to study cell lineage during development and as a tag to localize proteins in living cells. Other applications of GFP include assessment of protein protein interactions through the yeast two hybrid system and measurement of distance between proteins through fluorescence energy transfer (FRET) protocols. GFP technology has considerably contributed to a greater understanding of cellular physiology.

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Platelet-derived growth factors (PDGFs) have been implicated in the control of cell proliferation, survival and migration. The PDGF family of growth factors consists of five different disulphide-linked dimers built up of four different polypeptide chains encoded by four different genes. Theses isoforms, PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD, act via two receptor tyrosine kinases, PDGF receptors α and β. Thus far, gene-targeting experiments have been attempted to create knockout mice deficient for PDGFR-α or PDGFR-β. Those mice, however, died either at the embryonic stage or several days after birth. Platelet-derived growth factor receptors, PDGFR-α and PDGFR-β, have five extracellular immunoglobulin-like domains and an intracellular tyrosine kinase domain. Upon binding a PDGF, the receptors form homo- and heterodimers. Dimerization of the receptors juxtaposes the intracellular part of the receptors, which allow phosphorylation in trans between the two receptors in the complex. These autophosphorylation provide docking sites for downstream signal transduction molecules. More than 10 different SH2–domain-containing molecules have been shown to bind to different autophosphorylation sites in the PDGF α- and β-receptors. There are signal transduction molecules with enzymatic activity, such as PI3-kinase, PLC-γ, Src, SHP-2, GAP, as well as adaptor molecules such as Grb2, Shc, Nck, Grb7 and Crk, and Stats. Each of the different partners recruited by the activated receptor initiates different signaling pathways, making possible a great variety of cellular response.

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NCK1 is one of the adaptor proteins which mediate specific protein-protein interactions in signaling processes. Adaptor proteins usually contain several domains like SH2 (Src homology 2) and SH3 which allow specific interactions with other specific proteins.
NCK1 and NCK2 showing high sequence identity (68%) have three SH3 domains and a C-terminal SH2 domain. Both of them bind receptor tyrosine kinases such as PDGFR and other tyrosine phosphorylated proteins via their SH2 domains. Various molecules which interact with SH domains of Nck and regulate signaling process of actin cytoskeleton reorganization have been identified. Ncks are thought to have important functions in the development of mesodermal structures during embryogenesis, linked to a role in cell movement and cytoskeletal reorganization.
Nck also have a function in modulating mRNA translation at the level of initiation by interacting eukayotic initiation factor 2 (eIF2). Under the stressed conditions, protein synthesis is reduced by inhibiting the activity of eIF2 through the phosphorylation, transiently inhibiting recycling of eIF2 into its active form.

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Synuclein is a small, soluble protein primarily expressed in neural tissue. The synuclein family includes three known proteins: α-synuclein, β-synuclein, and γ-synuclein.
γ-Synuclein is a synuclein protein found primarily in the peripheral nervous system (in primary sensory neurons, sympathetic neurons, and motor neurons) and retina. γ-Synuclein expression in breast tumors is a marker for tumor progression.

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Well known as detoxification enzymes, the glutathione transferases (GST) also function in prostaglandin and steroid hormone synthesis. The enzymes are dimmers of 25kDa subunits. There are three major groups of GSTs: canonical(or cytosolic) GSTs(cGSTs), mitochondrial GSTs, and microsomal GSTs. GSTs play a role in the metabolism of drugs, pesticides and other xenobiotics.
GST is also a widely used fusion partner, since it offers both an easily detectable tag and a simple purification process that has a minimal effect on the biological function of the protein of interest. Recombinant hybrids containing a polypeptide fusion partner (termed “affinity tag”) to facilitate the purification of the target polypeptides are widely used. Epitope tags are useful for the labeling and detection of proteins using immunoblotting, IP and immunostaining techniques. Due to their small size, they are unlikely to affect the tagged protein’s biochemical properities. Numerous vectors containing GST-tags have been developed for both prokaryotic and eukaryotic systems over the past decade.

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Amyloid β (Aβ or A β) is a protein fragment of 39-43 amino acids that is the main constituent of amyloid plaques in the brains of Alzheimer's disease patients. Aβ is formed after sequential cleavage of the amyloid precursor protein (APP, transmembrane glycoprotein) by the β- and γ-secretases. . The major species generated are Aβ40 and Aβ42. The latter is more hydrophobic and more apt to aggregate and thus is considered to be primarily pathogenic, consistent with the phenotype of the major familial AD-causing mutations. Increases in either total Aβ levels or the relative concentration of the 42-amino acid form have been implicated in the pathogenesis of both familial and sporadic Alzheimer's disease. The 42-mers are the most amyloidogenic form of the peptide.

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The complement system is a crucial component of the innate immunity against microbial infection. Complement factor H, a 155 kDa plasma glycoprotein, is an essential regulatory protein that plays a critical role in the homeostasis of the complement system in plasma and in the protection of bystander host cells and tissues from damage by complement activation. Factor H binds to C3b, accelerates the decay of the alternative pathway C3-convertase and acts as a cofactor for the factor I-mediated proteolytic inactivation of C3b. In addition, factor H has multiple physiological activities 1) acts as an extracellular matrix component, 2) binds to cellular receptors of the integrin type, and 3) interacts with a wide selection of ligands, such as the C-reactive protein, thrombospondin, bone sialoprotein, osteopontin, and heparin. Complement factor H has revealed an association with two different renal diseases, glomerulonephritis and atypical hemolytic uremic syndrome (aHUS).

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Cyclin-dependent kinase 6 (CDK6) is a 40 kDa member of the CDK family of mitotic kinases involved in cell cycle progression. CDKs are the catalytic subunits of the cyclin/CDK complexes, which phosphorylate substrates on threonine/serine residues. CDK6 associates with the D-type cyclins and is important in the progression of cells from the G1-phase to the S-phase of the cell cycle. Loss of normal cell cycle regulation is the hallmark of human cancers, and alteration of the components involved in cell cycle regulation occurs in most human tumors. This suggests that CDK6 is an attractive target for the development of pharmacological agents for the treatment of cancer. Recently, several studies have indicated a novel role for cdk6 in differentiation, also.

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Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Fibronectins are involved in cell adhesion, cell motility, opsonization, wound healing, and maintenance of cell shape.

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Focal adhesion kinase subfamily consists of the non-receptor proline-rich protein tyrosine kinases (PTKs). Two members of the family are focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). These two kinases have molecular mass between 110-125 kDa and are closely related in their structure. The presence of two proline-rich motifs within the C-terminal domains is conserved.
FAK is a nonreceptor and nonmembrane associated PTK which does not contain Src homology 2 (SH2) or SH3 protein interaction domains. The centrally located kinase domain of FAK is flanked by large N- and C-terminal noncatalytic domains.
FAK links integrin receptors to intracellular signaling pathways that are important for cell growth, survival, and migration. Integrin receptor engagement with ligands such as fibronectin can stimulate FAK autophosphorylation which enables FAK to function within a network of integrin-stimulated signaling pathways leading to the activation of targets such as the ERK and JNK/mitogen-activated protein kinase pathways. Recent study reveals that FAK is essential for angiogenesis in the embryo, functions in heart development and modulates the response of cardiomyocytes to pressure overload in adult mice.

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Syk, Spleen tyrosine kinase, is expressed in a wide range of hematopoietic and non-hematopoietic cells and plays a key role in adaptive immune system, which is the immunoreceptor (B cell receptor and Fc-receptors) signaling pathways including Fcγ receptor-mediated phagocytosis. In hematopoietic cells such as B and T lymphocytes, natural killer cells, mast cells, macrophages and platelets, Syk is involved in the proximal signaling downstream of activated immunoreceptors (e.g. BCR, TCR, Fc receptors) containing immunoreceptor tyrosine-based activation motifs (ITAMs) to which it binds using its tandem SH2 domains. Activated and autophosphorylated Syk then phosphorylates its specific substrates including other enzymes and adaptor proteins, orchestrating a complex series of cellular responses such as cell proliferation, differentiation, survival and phagocytosis.

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IκB kinase β (IKKβ) is a component of a multiprotein kinase complex that regulates the activity of the transcription factor NF-κB. Activation of the IKK complex via upstream stimuli leads to phosphorylation and degradation of NF-κB bound IκB (Inhibitor of κB). Subsequently, free NF-κB dimers enter the nucleus and regulate the transcription of a variety of target genes involved in cell proliferation and differentiation, apoptosis, and inflammation, etc. The IKK complex consists of 2 highly homologous kinase subunits, IKKα and IKKβ, and a nonenzymatic regulatory component, IKKγ/NEMO. The relative contributions of IKKα and IKKβ to the signaling complex vary according to the requirements of the cell. IKKβ plays a predominant role in immune responses, while IKKα alone appears to be sufficient for at least some developmental systems. Recently, IKK/NF-κB signaling pathway was studied as therapeutic targets in cancer.

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Plasminogen, a 92kDa glycoprotein, is produced by the liver and is present in plasma and extracellular fluids. Plasminogen is the inactive precursor of plasmin, a potent serine protease involved in the dissolution of fibrin blood clots. Plasminogen can be converted into the active plasmin by plasminogen activators urokinase (uPA), tissue plasminogen activator (tPA), factor XII-dependent components. The plasmin system has been implicated in a variety of physiological and pathological processes such as fibrinolysis, tissue remodeling, cell migration, inflammation, and tumor invasion and metastasis. Hereditary defects of plasminogen is a predisposing risk factor for thromboembolic disease.

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Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11A. RAD50 may be required to bind DNA ends and hold them in close proximity. This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11A to prevent nucleolytic degradation past a given point. The complex may also be required for DNA damage signaling via activation of the ATM kinase. In telomeres the MRN complex may modulate t-loop formation.