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37-400: 7535 22637 ENSG00000115085 ENSMUSG00000026117 P43403 P43404 NM_001079 NM_207519 NM_001378594 NM_009539 NM_001289612 NM_001289765 NM_001289766 NP_001070 NP_997402 NP_001365523 NP_001276541 NP_001276694 NP_001276695 NP_033565 ZAP-70 ( Zeta-chain-associated protein kinase 70 ) is a protein normally expressed near

74-422: A Wright's stained peripheral blood smear , a normal lymphocyte has a large, dark-staining nucleus with little to no eosinophilic cytoplasm. In normal situations, the coarse, dense nucleus of a lymphocyte is approximately the size of a red blood cell (about 7  μm in diameter). Some lymphocytes show a clear perinuclear zone (or halo) around the nucleus or could exhibit a small clear zone to one side of

111-450: A central antiparallel β-sheet centered between two α-helices . Binding to phosphotyrosine -containing peptides involves a strictly-conserved Arg residue that pairs with the negatively-charged phosphate on the phosphotyrosine, and a surrounding pocket that recognizes flanking sequences on the target peptide. Compared to other signaling proteins, SH2 domains exhibit only a moderate degree of specificity for their target peptides, due to

148-840: A decrease in the entry of lymphocytes into lymph nodes, which can lead to a condition known as lymphocytosis, with a complete lymphocyte count of over 4000 per μl in adults or over 8000 per μl in children. This is unique in that many bacterial infections illustrate neutrophil-predominance instead. Lymphoproliferative disorders (LPD) encompass a diverse group of diseases marked by uncontrolled lymphocyte production, leading to issues like lymphocytosis, lymphadenopathy, and bone marrow infiltration. These disorders are common in immunocompromised individuals and involve abnormal proliferation of T and B cells, often resulting in immunodeficiency and immune system dysfunction. Various gene mutations, both iatrogenic and acquired, are implicated in LPD. One subtype, X-linked LPD,

185-606: A docking site to which a number of signaling proteins bind, including the SH2-domain-containing leukocyte protein of 76 kDa ( SLP-76 ). SLP-76 is also phosphorylated by ZAP-70, which requires its activation by Src family kinases . The final outcome of T cell activation is the transcription of several gene products which allow the T cells to differentiate, proliferate, and secrete a number of cytokines . Due to its role in lymphocyte signaling, ZAP-70 has been associated with several diseases affecting lymphocytes. ZAP-70 expression

222-587: A form of autosomal recessive immune deficiency named combined immunodeficiency . Patients afflicted with combined immunodeficiency have a normal lymphocyte count, but they have low concentrations of T helper cells and cytotoxic T cells. Patients were also found to have irregular lymphocyte proliferation responses. These effects suggest that a deficiency in ZAP-70 results in decreased rates of T cell activation and subsequent signal transductions. ZAP-70 has been shown to interact with: Lymphocyte A lymphocyte

259-417: A hierarchical fashion as well as in a more plastic fashion. The formation of lymphocytes is known as lymphopoiesis . In mammals , B cells mature in the bone marrow , which is at the core of most bones . In birds , B cells mature in the bursa of Fabricius , a lymphoid organ where they were first discovered by Chang and Glick, (B for bursa) and not from bone marrow as commonly believed. T cells migrate to

296-572: A larger structure (called a supramolecular assembly ). Using molecular biology techniques, fusion proteins of specific enzymes and SH2 domains have been created, which can bind to each other to form protein assemblies. Since SH2 domains require phosphorylation in order for binding to occur, the use of kinase and phosphatase enzymes gives researchers control over whether protein assemblies will form or not. High affinity engineered SH2 domains have been developed and utilized for protein assembly applications. The goal of most protein assembly formation

333-433: A strong and rapid response if the same pathogen is detected again; this is known as acquired immunity . NK cells are a part of the innate immune system and play a major role in defending the host from tumors and virally infected cells. NK cells modulate the functions of other cells, including macrophages and T cells, and distinguish infected cells and tumors from normal and uninfected cells by recognizing changes of

370-421: A surface molecule called major histocompatibility complex (MHC) class I . NK cells are activated in response to a family of cytokines called interferons . Activated NK cells release cytotoxic (cell-killing) granules which then destroy the altered cells. They are named "natural killer cells" because they do not require prior activation in order to kill cells which are missing MHC class I. The X lymphocyte

407-463: A wide array of disorders involving B-cell (e.g., chronic lymphocytic leukemia) and T-cell (e.g., Sezary syndrome) abnormalities, each presenting distinct challenges in diagnosis and management. A low normal to low absolute lymphocyte concentration is associated with increased rates of infection after surgery or trauma . One basis for low T cell lymphocytes occurs when the human immunodeficiency virus (HIV) infects and destroys T cells (specifically,

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444-501: Is a critical component of T cell activation and development. ZAP-70 expression in B cells is correlated with the development of chronic lymphocytic leukemia (CLL). The T cell receptor has no innate enzymatic activity. Due to this, T cell receptors rely on signaling molecules to transduce a signal from the cell membrane. ZAP-70 is a critical cytoplasmic tyrosine kinase that initiates a signal pathway downstream of an activated T cell receptor. T lymphocytes are activated by engagement of

481-476: Is a member of the protein- tyrosine kinase family and is a close homolog of SYK . SYK and ZAP70 share a common evolutionary origin and split from a common ancestor in the jawed vertebrates . The importance of ZAP-70 in T cell activation was determined when comparing ZAP-70 expression in patients with SCID ( severe combined immunodeficiency ). ZAP-70 deficient individuals were found to have no functioning T cells in their peripheral blood, suggesting that ZAP-70

518-403: Is a reported cell type expressing both a B-cell receptor and T-cell receptor and is hypothesized to be implicated in type 1 diabetes. Its existence as a cell type has been challenged by two studies. However, the authors of original article pointed to the fact that the two studies have detected X cells by imaging microscopy and FACS as described. Additional studies are required to determine

555-654: Is a significant indicator of the survival of lymphocytes and has been notably associated with chronic lymphocytic leukemia (CLL). CLL is a cancer that develops from overproduction of B cells in the bone marrow. In people with CLL, higher levels of ZAP-70 confers a worse prognosis; CLL patients that are positive for the marker ZAP-70 have an average survival of 8 years, whereas those that are negative for ZAP-70 have an average survival of more than 25 years. Many patients, especially older ones, with slowly progressing disease can be reassured and may not need any treatment in their lifetimes. In individuals with CLL, higher levels of ZAP-70

592-487: Is a type of white blood cell (leukocyte) in the immune system of most vertebrates . Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity ), B cells (for humoral , antibody -driven adaptive immunity ), and innate lymphoid cells (ILCs; "innate T cell-like" cells involved in mucosal immunity and homeostasis), of which natural killer cells are an important subtype (which functions in cell-mediated , cytotoxic innate immunity ). They are

629-471: Is associated with a higher number of malignant B cells activated. Increased expression of ZAP-70 in B cell malignancies is correlated with increased association between malignant B cells and the immune environment, suggesting a complex role for ZAP-70 in B cell signaling. In systemic lupus erythematosus , the Zap-70 receptor pathway is missing and the homolog Syk takes its place. ZAP-70 deficiency results in

666-405: Is linked to mutations in the X chromosome, predisposing individuals to natural killer cell LPD and T-cell LPD. Additionally, conditions like common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), and certain viral infections elevate the risk of LPD. Treatment methods, such as immunosuppressive drugs and tissue transplantation, can also increase susceptibility. LPDs encompass

703-565: The CD4 subgroup of T lymphocytes, which become helper T cells). Without the key defense that these T cells provide, the body becomes susceptible to opportunistic infections that otherwise would not affect healthy people. The extent of HIV progression is typically determined by measuring the percentage of CD4 T cells in the patient's blood – HIV ultimately progresses to acquired immune deficiency syndrome (AIDS). The effects of other viruses or lymphocyte disorders can also often be estimated by counting

740-466: The ELISPOT or secretion assay techniques can be used. In the circulatory system , they move from lymph node to lymph node. This contrasts with macrophages , which are rather stationary in the nodes. A lymphocyte count is usually part of a peripheral complete blood cell count and is expressed as the percentage of lymphocytes to the total number of white blood cells counted. A general increase in

777-545: The CD3 complex and phosphorylates the tyrosines in the immunoreceptor tyrosine-based activation motifs (ITAMS), creating a docking site for ZAP-70. The most important member of the CD3 family is CD3-zeta , to which ZAP-70 binds (hence the abbreviation). The tandem SH2-domains of ZAP-70 are engaged by the doubly phosphorylated ITAMs of CD3-zeta, which positions ZAP-70 to phosphorylate the transmembrane protein linker for activation of T cells (LAT). Phosphorylated LAT, in turn, serves as

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814-545: The SH2-containing protein, depending on the types of interactions formed between the SH2 domain and other domains of the enzyme. Mutations that disrupt the structural stability of the SH2 domain, or that affect the binding of the phosphotyrosine peptide of the target, are involved in a range of diseases including X-linked agammaglobulinemia and severe combined immunodeficiency . SH2 domains are not present in yeast and appear at

851-546: The T cell receptor with processed antigen fragments presented by professional antigen presenting cells (i.e. macrophages , dendritic cells , Langerhans cells and B cells ) via the MHC . Upon this activation, the TCR co-receptor CD4 (expressed on T helper cells ) or CD8 (expressed on cytotoxic T cells ) binds to the MHC, activating the co-receptor associated tyrosine kinase Lck . Lck is moved near

888-434: The antigen, either by releasing antibodies (in the case of B cells), cytotoxic granules ( cytotoxic T cells ) or by signaling to other cells of the immune system ( helper T cells ). Memory T cells remain in the peripheral tissues and circulation for an extended time ready to respond to the same antigen upon future exposure; they live weeks to several years, which is very long compared to other leukocytes. Microscopically, in

925-480: The blood stream and mature in a distinct primary organ, called the thymus . Following maturation, the lymphocytes enter the circulation and peripheral lymphoid organs (e.g. the spleen and lymph nodes ) where they survey for invading pathogens and/or tumor cells. The lymphocytes involved in adaptive immunity (i.e. B and T cells) differentiate further after exposure to an antigen ; they form effector and memory lymphocytes. Effector lymphocytes function to eliminate

962-662: The boundary between protozoa and animalia in organisms such as the social amoeba Dictyostelium discoideum . A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 115 proteins encoded by the human genome, representing a rapid rate of evolutionary expansion among the SH2 domains. A large number of SH2 domain structures have been solved and many SH2 proteins have been knocked out in mice. SH2 domains, and other binding domains , have been used in protein engineering to create protein assemblies. Protein assemblies are formed when several proteins bind to one another to create

999-432: The function or activity of the SH2-containing protein. The SH2 domain may be considered the prototypical modular protein-protein interaction domain, allowing the transmission of signals controlling a variety of cellular functions. SH2 domains are especially common in adaptor proteins that aid in the signal transduction of receptor tyrosine kinase pathways. SH2 domains contain about 100 amino acid residues and exhibit

1036-445: The immune response, while other T cells, called cytotoxic T cells , produce toxic granules that contain powerful enzymes which induce the death of pathogen-infected cells. Following activation, B cells and T cells leave a lasting legacy of the antigens they have encountered, in the form of memory cells . Throughout the lifetime of an animal, these memory cells will "remember" each specific pathogen encountered, and are able to mount

1073-532: The main type of cell found in lymph , which prompted the name "lymphocyte" (with cyte meaning cell). Lymphocytes make up between 18% and 42% of circulating white blood cells. The three major types of lymphocyte are T cells , B cells and natural killer (NK) cells. They can also be classified as small lymphocytes and large lymphocytes based on their size and appearance. Lymphocytes can be identified by their large nucleus. T cells ( thymus cells) and B cells ( bone marrow - or bursa -derived cells ) are

1110-745: The major cellular components of the adaptive immune response. T cells are involved in cell-mediated immunity , whereas B cells are primarily responsible for humoral immunity (relating to antibodies ). The function of T cells and B cells is to recognize specific "non-self" antigens, during a process known as antigen presentation . Once they have identified an invader, the cells generate specific responses that are tailored maximally to eliminate specific pathogens or pathogen-infected cells. B cells respond to pathogens by producing large quantities of antibodies which then neutralize foreign objects like bacteria and viruses . In response to pathogens some T cells, called T helper cells , produce cytokines that direct

1147-416: The nature and properties of X cells (also called dual expressers). Mammalian stem cells differentiate into several kinds of blood cell within the bone marrow . This process is called haematopoiesis . All lymphocytes originate, during this process, from a common lymphoid progenitor before differentiating into their distinct lymphocyte types. The differentiation of lymphocytes follows various pathways in

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1184-478: The nucleus. Polyribosomes are a prominent feature in the lymphocytes and can be viewed with an electron microscope . The ribosomes are involved in protein synthesis , allowing the generation of large quantities of cytokines and immunoglobulins by these cells. It is impossible to distinguish between T cells and B cells in a peripheral blood smear. Normally, flow cytometry testing is used for specific lymphocyte population counts. This can be used to determine

1221-505: The number of lymphocytes is known as lymphocytosis , whereas a decrease is known as lymphocytopenia . An increase in lymphocyte concentration is usually a sign of a viral infection (in some rare case, leukemias are found through an abnormally raised lymphocyte count in an otherwise normal person). A high lymphocyte count with a low neutrophil count might be caused by lymphoma . Pertussis toxin (PTx) of Bordetella pertussis , formerly known as lymphocytosis-promoting factor, causes

1258-571: The numbers of lymphocytes present in the blood . In some cancers, such as melanoma and colorectal cancer , lymphocytes can migrate into and attack the tumor . This can sometimes lead to regression of the primary tumor. SH2-domains The SH2 ( S rc H omology 2 ) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains bind to phosphorylated tyrosine residues on other proteins, modifying

1295-402: The percentage of lymphocytes that contain a particular combination of specific cell surface proteins, such as immunoglobulins or cluster of differentiation (CD) markers or that produce particular proteins (for example, cytokines using intracellular cytokine staining (ICCS)). In order to study the function of a lymphocyte by virtue of the proteins it generates, other scientific techniques like

1332-410: The relative weakness of the interactions with the flanking sequences. Over 100 human proteins are known to contain SH2 domains. A variety of tyrosine-containing sequences have been found to bind SH2 domains and are conserved across a wide range of organisms, performing similar functions. Binding of a phosphotyrosine-containing protein to an SH2 domain may lead to either activation or inactivation of

1369-472: The surface membrane of lymphocytes ( T cells , natural killer cells , and a subset of B cells ). It is most prominently known to be recruited upon antigen binding to the T cell receptor (TCR), and it plays a critical role in T cell signaling. ZAP-70 was initially discovered in TCR-stimulated Jurkat cells , an immortal line of human T lymphocytes, in 1991. Its molecular weight is 70 kDa , and it

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