The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Notch signaling plays a pivotal role in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. The notch cascade consists of notch and notch ligands, as well as intracellular proteins transmitting the notch signal to the cell's nucleus. In mammalian cells, there are four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4, which display both redundant and unique functions. Notch receptors are large single pass Type I transmembrane proteins. The extracellular domain of all Notch proteins contains 29–36 tandem epidermal growth factor (EGF)-like repeats, some of which mediate interactions with ligand. After specific ligand binding, the intracellular part of the Notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor RBP-J. In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. Notch signaling is dysregulated in many cancers, and faulty notch signaling is implicated in many diseases including CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy), T-ALL (T-cell acute lymphoblastic leukemia), Alagille syndrome, MS (Multiple Sclerosis), and myriad other disease states.
|Cytokine & Receptor Information|
Cytokines are a large group of proteins, peptides or glycoproteins that are secreted by specific cells of immune system. Cytokines are a category of signaling molecules that mediate and regulate immunity, inflammation and hematopoiesis. Cytokines are produced throughout the body by cells of diverse embryological origin. Cytokine is a general name; other names are defined based on their presumed function, cell of secretion, or target of action. For example, cytokines made by lymphocytes can also be referred to as lymphokines, while interleukins are made by one leukocyte and act on other leukocytes. And chemokines are cytokines with chemotactic activities.
Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action).
Several main groups of cytokines include: interleukins, chemokines, interferons, tumor necrosis factors (TNFs), colony-stimulating factors (CSFs), and TGF-beta superfamily members. Interleukins are a group of cytokines that were first seen to be expressed by leukocytes. They modulate inflammation and immunity by regulating growth, mobility and differentiation of lymphoid and other cells. Chemokines are chemotactic cytokines with the ability to induce directed chemotaxis in nearby responsive cells. Stimulated by pro-inflammatory cytokines infected tissues release chemokines, and chemokine gradients induce leukocytes to move between endothelial cells and pass the basement membrane into the infected tissues. Interferons are cytokines which are made and released by the cells of most vertebrates in response to the presence of pathogens (such as viruses, bacteria, or parasites, or tumor cells). Interferons play critical role in host defense mechanisms. The tumor necrosis factor (TNF) superfamily of cytokines act through ligand-mediated trimerization, causing recruitment of several intracellular adaptors to activate multiple signal transduction pathways for cell survival, death, and differentiation. Colony-stimulating factors (CSFs), also called haematopoietic growth factors, are secreted glycoproteins which regulate bone marrow production of circulating red and white cells, and platelets.
An important part of Cytokines’ action on the immune system is to stimulate immune cell proliferation and differentiation. Cytokines involved in this function include interleukin 1 (IL-1), which activates T cells; IL-2, which stimulates proliferation of antigen-activated T and B cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells; and other cytokines such as, interferon gamma, IL-3, IL-7 and colony-stimulating factor (GM-CSF).
Cytokines act on their target cells by binding specific membrane receptors. The receptors and their corresponding cytokines have been divided into several families based on their structure and activities. Type I cytokine receptors have certain conserved motifs in their extracellular amino-acid domain, and lack an intrinsic protein tyrosine kinase activity. Type II cytokine receptors are multimeric receptors composed of heterologous subunits, and are receptors mainly for interferons. The extracellular domains of type II cytokine receptors share structural similarities in their ligand-binding domain. Some cytokine receptors belong to the immunoglobulin superfamily, such as IL-1R alpha, IL-1R beta, IL-6R alpha, SCFR, c-kit, etc. Other cytokine receptors include TNF receptor family, chemokine receptors, and TGF-beta receptors.
Cytokines have been proved useful in immune-based therapies. For example, interferon-alpha, a cytokine with broad antiviral properties, has been proven to be useful in treating cancers, such as malignant melanoma. Cytokine therapy is not merely a tool of the future. In fact, several cytokine therapies are now routinely used by many people living with HIV.