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| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| Biochemical cascade | 6/9 | https://en.wikipedia.org/wiki/Biochemical_cascade | reference | science, encyclopedia | 2026-05-05T10:46:07.942614+00:00 | kb-cron |
=== Spermatozoon === Spermatozoon is the male gamete. After ejaculation this cell is not mature, so it can not fertilize the oocyte. To have the ability to fertilize the female gamete, this cell suffers capacitation and acrosome reaction in female reproductive tract. The signaling pathways best described for spermatozoon involve these processes. The cAMP/PKA signaling pathway leads to sperm cells capacitation; however, adenylyl cyclase in sperm cells is different from the somatic cells. Adenylyl cyclase in spermatozoon does not recognize G proteins, so it is stimulated by bicarbonate and Ca2+ ions. Then, it converts adenosine triphosphate into cyclic AMP, which activates Protein kinase A. PKA leads to protein tyrosine phosphorylation. Phospholipase C (PLC) is involved in acrosome reaction. ZP3 is a glycoprotein present in zona pelucida and it interacts with receptors in spermatozoon. So, ZP3 can activate G protein coupled receptors and tyrosine kinase receptors, that leads to production of PLC. PLC cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate. IP3 is released as a soluble structure into the cytosol and DAG remains bound to the membrane. IP3 binds to IP3 receptors, present in acrosome membrane. In addition, calcium and DAG together work to activate protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. These actions cause an increase in cytosolic concentration of Ca2+ that leads to dispersion of actin and consequently promotes plasmatic membrane and outer acrosome membrane fusion. Progesterone is a steroid hormone produced in cumulus oophorus. In somatic cells it binds to receptors in nucleus; however, in spermatozoon its receptors are present in plasmatic membrane. This hormone activates AKT that leads to activation of other protein kinases, involved in capacitation and acrosome reaction. When ROS (reactive oxygen species) are present in high concentration, they can affect the physiology of cells, but when they are present in moderated concentration they are important for acrosome reaction and capacitation. ROS can interact with cAMP/PKA and progesterone pathway, stimulating them. ROS also interacts with ERK pathway that leads to activation of Ras, MEK and MEK-like proteins. These proteins activate protein tyrosine kinase (PTK) that phosphorylates various proteins important for capacitation and acrosome reaction.
=== Embryos === Various signalling pathways, as FGF, WNT and TGF-β pathways, regulate the processes involved in embryogenesis. FGF (Fibroblast Growth Factor) ligands bind to receptors tyrosine kinase, FGFR (Fibroblast Growth Factor Receptors), and form a stable complex with co-receptors HSPG (Heparan Sulphate Proteoglycans) that will promote autophosphorylation of the intracellular domain of FGFR and consequent activation of four main pathways: MAPK/ERK, PI3K, PLCγ and JAK/STAT.
MAPK/ERK (Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase) regulates gene transcription through successive kinase phosphorylation and in human embryonic stem cells it helps maintaining pluripotency. However, in the presence of Activin A, a TGF-β ligand, it causes the formation of mesoderm and neuroectoderm. Phosphorylation of membrane phospholipids by PI3K (Phosphatidylinositol 3-Kinase) results in activation of AKT/PKB (Protein Kinase B). This kinase is involved in cell survival and inhibition of apoptosis, cellular growth and maintenance of pluripotency, in embryonic stem cells. PLCγ (Phosphoinositide Phospholipase C γ) hydrolyzes membrane phospholipids to form IP3 (Inositoltriphosphate) and DAG (Diacylglycerol), leading to activation of kinases and regulating morphogenic movements during gastrulation and neurulation. STAT (Signal Trandsducer and Activator of Transcription) is phosphorylated by JAK (Janus Kinase) and regulates gene transcription, determining cell fates. In mouse embryonic stem cells, this pathway helps maintaining pluripotency. The WNT pathway allows β-catenin function in gene transcription, once the interaction between WNT ligand and G protein-coupled receptor Frizzled inhibits GSK-3 (Glycogen Synthase Kinase-3) and thus formation of β-catenin destruction complex. Although there is some controversy about the effects of this pathway in embryogenesis, it is thought that WNT signalling induces primitive streak, mesoderm and endoderm formation. In TGF-β (Transforming Growth Factor β) pathway, BMP (Bone Morphogenic Protein), Activin and Nodal ligands bind to their receptors and activate Smads that bind to DNA and promote gene transcription. Activin is necessary for mesoderm and specially endoderm differentiation, and Nodal and BMP are involved in embryo patterning. BMP is also responsible for formation of extra-embryonic tissues before and during gastrulation, and for early mesoderm differentiation, when Activin and FGF pathways are activated.
== Pathway construction == Pathway building has been performed by individual groups studying a network of interest (e.g., immune signaling pathway) as well as by large bioinformatics consortia (e.g., the Reactome Project) and commercial entities (e.g., Ingenuity Systems). Pathway building is the process of identifying and integrating the entities, interactions, and associated annotations, and populating the knowledge base. Pathway construction can have either a data-driven objective (DDO) or a knowledge-driven objective (KDO). Data-driven pathway construction is used to generate relationship information of genes or proteins identified in a specific experiment such as a microarray study. Knowledge-driven pathway construction entails development of a detailed pathway knowledge base for particular domains of interest, such as a cell type, disease, or system. The curation process of a biological pathway entails identifying and structuring content, mining information manually and/or computationally, and assembling a knowledgebase using appropriate software tools. A schematic illustrating the major steps involved in the data-driven and knowledge-driven construction processes. For either DDO or KDO pathway construction, the first step is to mine pertinent information from relevant information sources about the entities and interactions. The information retrieved is assembled using appropriate formats, information standards, and pathway building tools to obtain a pathway prototype. The pathway is further refined to include context-specific annotations such as species, cell/tissue type, or disease type. The pathway can then be verified by the domain experts and updated by the curators based on appropriate feedback. Recent attempts to improve knowledge integration have led to refined classifications of cellular entities, such as GO, and to the assembly of structured knowledge repositories. Data repositories, which contain information regarding sequence data, metabolism, signaling, reactions, and interactions are a major source of information for pathway building. A few useful databases are described in the following table.