Biochemical cascade

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Signaling cascade
)

A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of

chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that is transduced to the cell interior through second messengers which amplify the signal and transfer it to effector molecules, causing the cell to respond to the initial stimulus.[1] Most biochemical cascades are series of events, in which one event triggers the next, in a linear fashion. At each step of the signaling cascade, various controlling factors are involved to regulate cellular actions, in order to respond effectively to cues about their changing internal and external environments.[1]

An example would be the

basal cell carcinoma.[3]
Recent studies point to the role of hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues. The pathway has also been implicated in the development of some cancers. Drugs that specifically target hedgehog signaling to fight diseases are being actively developed by a number of pharmaceutical companies.

Introduction

Signaling cascades

Cells require a full and functional cellular machinery to live. When they belong to complex multicellular organisms, they need to communicate among themselves and work for symbiosis in order to give life to the organism. These communications between cells triggers intracellular signaling cascades, termed signal transduction pathways, that regulate specific cellular functions. Each signal transduction occurs with a primary extracellular messenger that binds to a transmembrane or nuclear receptor, initiating intracellular signals. The complex formed produces or releases second messengers that integrate and adapt the signal, amplifying it, by activating molecular targets, which in turn trigger effectors that will lead to the desired cellular response.[4]

Transductors and effectors

Signal transduction is realized by activation of specific receptors and consequent production/delivery of second messengers, such as Ca2+ or cAMP. These molecules operate as signal transducers, triggering intracellular cascades and in turn amplifying the initial signal.[4] Two main signal transduction mechanisms have been identified, via

ligand-gated ion channels (LGICs).[1][4]
Second messengers can be classified into three classes:

  1. Hydrophilic/cytosolic – are soluble in water and are localized at the cytosol, including cAMP,
    cADPR and S1P. Their main targets are protein kinases as PKA and PKG, being then involved in phosphorylation mediated responses.[4]
  2. Hydrophobic/membrane-associated – are insoluble in water and membrane-associated, being localized at intermembrane spaces, where they can bind to membrane-associated effector proteins. Examples:
    DAG, phosphatidic acid, arachidonic acid and ceramide. They are involved in regulation of kinases and phosphatases, G protein associated factors and transcriptional factors.[4]
  3. Gaseous – can be widespread through cell membrane and cytosol, including nitric oxide and carbon monoxide. Both of them can activate cGMP and, besides of being capable of mediating independent activities, they also can operate in a coordinated mode.[4]

Cellular response

The cellular response in signal transduction cascades involves alteration of the expression of effector genes or activation/inhibition of targeted proteins. Regulation of protein activity mainly involves phosphorylation/dephosphorylation events, leading to its activation or inhibition. It is the case for the vast majority of responses as a consequence of the binding of the primary messengers to membrane receptors. This response is quick, as it involves regulation of molecules that are already present in the cell. On the other hand, the induction or repression of the expression of genes requires the binding of

DAG or Ca2+ could also induce or repress gene expression, via transcriptional factors. This response is slower than the first because it involves more steps, like transcription of genes and then the effect of newly formed proteins in a specific target. The target could be a protein or another gene.[1][4][5]

Examples of biochemical cascades

In

coagulation cascade of secondary hemostasis is the primary pathway leading to fibrin formation, and thus, the initiation of blood coagulation. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factors are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin.[6]

Another example,

basal cell carcinoma.[3] Recent studies point to the role of hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues. The pathway has also been implicated in the development of some cancers. Drugs that specifically target hedgehog signaling to fight diseases are being actively developed by a number of pharmaceutical companies.[7]
Most biochemical cascades are series of events, in which one event triggers the next, in a linear fashion.

Biochemical cascades include:

Conversely, negative cascades include events that are in a circular fashion, or can cause or be caused by multiple events.[8] Negative cascades include:

Cell-specific biochemical cascades

Epithelial cells

Adhesion is an essential process to epithelial cells so that epithelium can be formed and cells can be in permanent contact with extracellular matrix and other cells. Several pathways exist to accomplish this communication and adhesion with environment. But the main signalling pathways are the cadherin and integrin pathways.[9]
The
Wnt signalling is activated, β-catenin degradation is inhibited and it is translocated to the nucleus where it forms a complex with transcription factors. This leads to activation of genes responsible for cell proliferation and survival. So the cadherin-catenin complex is essential for cell fate regulation.[11][12]
Akt activation and this inhibits pro-apoptotic factors like BAD and Bax. When adhesion through integrins do not occur the pro-apoptotic factors are not inhibited and resulting in apoptosis.[13][14]

Hepatocytes

The

hepatic lobule, because concentrations of oxygen and toxic substances present in the hepatic sinusoids change from periportal zone to centrilobular zone10. The hepatocytes of the intermediate zone have the appropriate morphological and functional features since they have the environment with average concentrations of oxygen and other substances.[15]
This specialized cell is capable of:[16]

  1. Via
    PKB and PLC /IP3
  2. Expression of enzymes for synthesis, storage and distribution of glucose
  1. Via JAK /STAT /APRE (acute phase response element)
  2. Expression of C-reactive protein, globulin protease inhibitors, complement, coagulation and fibrinolytic systems and iron homeostasis
  1. Via
    HAMP
  2. Hepcidin expression
  1. Via LXR /LXRE (LXR response element)
  2. Expression of
    CETP, FAS and LPL
  1. Via LXR /LXRE
  2. Expression of
    ABC transporters
  1. Via LXR /LXRE
  2. Expression of
    ABC transporters
  • Endocrine production
  1. Via JAK/STAT /GHRE (growth hormone response element)
IGF-1 and IGFBP-3
expression
  1. Via THR/THRE (thyroid hormone response element)[4][24][25][26]
Angiotensinogen
expression
  1. Via
    PI3K/FAK
  2. Cell growth, proliferation, survival, invasion and motility

The hepatocyte also regulates other functions for constitutive synthesis of proteins (

thyroxine.[15][30]

Neurons

purinergic receptors, P1 binding to adenosine, and P2 binding to ATP or ADP, presenting different signalling cascades.[31][32]
The
Nrf2/ARE signalling pathway has a fundamental role at fighting against oxidative stress, to which neurons are especially vulnerable due to its high oxygen consumption and high lipid content. This neuroprotective pathway involves control of neuronal activity by perisynaptic astrocytes and neuronal glutamate release, with the establishment of tripartite synapses. The Nrf2/ARE activation leads to a higher expression of enzymes involved in glutathione syntheses and metabolism, that have a key role in antioxidant response.[33][34][35][36]
The LKB1/NUAK1 signalling pathway regulates terminal axon branching at cortical neurons, via local immobilized mitochondria capture. Besides NUAK1, LKB1 kinase acts under other effectors enzymes as SAD-A/B and MARK, therefore regulating neuronal polarization and axonal growth, respectively. These kinase cascades implicates also Tau and others MAP.[37][38][39] An extended knowledge of these and others neuronal pathways could provide new potential therapeutic targets for several neurodegenerative chronic diseases as
amyotrophic lateral sclerosis.[31][32][33]

Blood cells

The

hematopoiesis
. The
vasodilators, like nitric oxide (NO) and prostacyclin (PGI2).[40][41]
The current model of
small GTPases are involved in the principal leukocyte signaling pathways underlying chemokine-stimulated integrin-dependent adhesion, and have important roles in regulating cell shape, adhesion and motility.[43]

The leukocyte adhesion cascade steps and the key molecules involved in each step

After a vascular injury occurs,

platelets
to each other. The increase of cytosolic calcium also leads to shape change and TxA2 synthesis, leading to signal amplification.

Lymphocytes

The main goal of biochemical cascades in

c-Jun) and btk (can also activate PLC).[45][53]

Bones

Wnt signaling pathway

The Wnt signaling pathway can be divided in canonical and non-canonical. The canonical signaling involves binding of Wnt to Frizzled and LRP5 co-receptor, leading to GSK3 phosphorylation and inhibition of β-catenin degradation, resulting in its accumulation and translocation to the nucleus, where it acts as a transcription factor. The non-canonical Wnt signaling can be divided in planar cell polarity (PCP) pathway and Wnt/calcium pathway. It is characterized by binding of Wnt to Frizzled and activation of G proteins and to an increase of intracellular levels of calcium through mechanisms involving PKC 50.[54] The Wnt signaling pathway plays a significant role in osteoblastogenesis and bone formation, inducing the differentiation of mesenquimal pluripotent cells in osteoblasts and inhibiting the RANKL/RANK pathway and osteoclastogenesis.[55]

RANKL/RANK signaling pathway

RANKL is a member of the TNF superfamily of ligands. Through binding to the RANK receptor it activates various molecules, like NF-kappa B, MAPK, NFAT and PI3K52. The RANKL/RANK signaling pathway regulates osteoclastogenesis, as well as, the survival and activation of osteoclasts.[56][57]

Adenosine signaling pathway

Adenosine is very relevant in bone metabolism, as it plays a role in formation and activation of both osteoclasts and osteoblasts. Adenosine acts by binding to purinergic receptors and influencing adenylyl cyclase activity and the formation of cAMP and PKA 54.[58] Adenosine may have opposite effects on bone metabolism, because while certain purinergic receptors stimulate adenylyl cyclase activity, others have the opposite effect.[58][59] Under certain circumstances adenosine stimulates bone destruction and in other situations it promotes bone formation, depending on the purinergic receptor that is being activated.

Stem cells

Self-renewal and differentiation abilities are exceptional properties of stem cells. These cells can be classified by their differentiation capacity, which progressively decrease with development, in totipotents, pluripotents, multipotents and unipotents.[60]

Self-renewal process is highly regulated from cell cycle and genetic transcription control. There are some signaling pathways, such as LIF/JAK/STAT3 (Leukemia inhibitory factor/Janus kinase/Signal transducer and activator of transcription 3) and BMP/SMADs/Id (Bone morphogenetic proteins/ Mothers against decapentaplegic/ Inhibitor of differentiation), mediated by transcription factors, epigenetic regulators and others components, and they are responsible for self-renewal genes expression and inhibition of differentiation genes expression, respectively.[61]

At cell cycle level there is an increase of complexity of the mechanisms in somatic stem cells. However, it is observed a decrease of self-renewal potential with age. These mechanisms are regulated by

p16Ink4a-CDK4/6-Rb and p19Arf-p53-P21Cip1 signaling pathways. Embryonic stem cells have constitutive cyclin E-CDK2 activity, which hyperphosphorylates and inactivates Rb. This leads to a short G1 phase of the cell cycle with rapid G1-S transition and little dependence on mitogenic signals or D cyclins for S phase entry. In fetal stem cells, mitogens promote a relatively rapid G1-S transition through cooperative action of cyclin D-CDK4/6 and cyclin E-CDK2 to inactivate Rb family proteins. p16Ink4a and p19Arf expression are inhibited by Hmga2-dependent chromatin regulation. Many young adult stem cells are quiescent most of the time. In the absence of mitogenic signals, cyclin-CDKs and the G1-S transition are suppressed by cell cycle inhibitors including Ink4 and Cip/Kip family proteins. As a result, Rb is hypophosphorylated and inhibits E2F, promoting quiescence in G0-phase of the cell cycle. Mitogen stimulation mobilizes these cells into cycle by activating cyclin D expression. In old adult stem cells, let-7 microRNA expression increases, reducing Hmga2 levels and increasing p16Ink4a and p19Arf levels. This reduces the sensitivity of stem cells to mitogenic signals by inhibiting cyclin-CDK complexes. As a result, either stem cells cannot enter the cell cycle, or cell division slows in many tissues.[62]

Extrinsic regulation is made by signals from the niche, where stem cells are found, which is able to promote quiescent state and cell cycle activation in somatic stem cells.[63] Asymmetric division is characteristic of somatic stem cells, maintaining the reservoir of stem cells in the tissue and production of specialized cells of the same.[64]

Stem cells show an elevated therapeutic potential, mainly in hemato-oncologic pathologies, such as leukemia and lymphomas. Little groups of stem cells were found into tumours, calling cancer stem cells. There are evidences that these cells promote tumor growth and metastasis.[65]

Oocytes

The

assisted reproduction procedures
, facilitating conception.

Spermatozoon

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.[82][83][84]
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.[85][86]
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.[87][88]
When
protein tyrosine kinase (PTK) that phosphorylates various proteins important for capacitation and acrosome reaction.[89][90]

Embryos

Various signalling pathways, as FGF,

embryogenesis
.

MAPK/ERK, PI3K, PLCγ and JAK/STAT.[91][92][93]

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.[93][99][100] 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.[100]
In
Activin and Nodal ligands bind to their receptors and activate Smads that bind to DNA and promote gene transcription.[93][101][102] 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.[101][102][103]

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.[104] 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.[105] A schematic illustrating the major steps involved in the data-driven and knowledge-driven construction processes.[104]

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.[106] 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.[107] Data repositories, which contain information regarding sequence data, metabolism, signaling, reactions, and interactions are a major source of information for pathway building.[108] A few useful databases are described in the following table.[104]

Database Curation Type GO Annotation (Y/N) Description
1. Protein-protein interactions databases
BIND Manual Curation N 200,000 documented biomolecular interactions and complexes
MINT Manual Curation N Experimentally verified interactions
HPRD Manual Curation N Elegant and comprehensive presentation of the interactions, entities and evidences
MPact Manual and Automated Curation N Yeast interactions. A part of MIPS
DIP[permanent dead link] Manual and Automated Curation Y Experimentally determined interactions
IntAct Manual Curation Y Database and analysis system of binary and multi-protein interactions
PDZBase Manual Curation N PDZ Domain containing proteins
GNPV[permanent dead link] Manual and Automated Curation Y Based on specific experiments and literature
BioGrid Manual Curation Y Physical and genetic interactions
UniHi Manual and Automated Curation Y Comprehensive human protein interactions
OPHID Manual Curation Y Combines PPI from BIND, HPRD, and MINT
2. Metabolic Pathway databases
EcoCyc Manual and Automated Curation Y Entire genome and biochemical machinery of E. Coli
MetaCyc Manual Curation N Pathways of over 165 species
HumanCyc Manual and Automated Curation N Human metabolic pathways and the human genome
BioCyc Manual and Automated Curation N Collection of databases for several organism
3. Signaling Pathway databases
KEGG Manual Curation Y Comprehensive collection of pathways such as human disease, signaling, genetic information processing pathways. Links to several useful databases
PANTHER Manual Curation N Compendium of metabolic and signaling pathways built using CellDesigner. Pathways can be downloaded in SBML format
Reactome Manual Curation Y Hierarchical layout. Extensive links to relevant databases such as NCBI, ENSEMBL, UNIPROT, HAPMAP, KEGG, CHEBI, PubMed, GO. Follows PSI-MI standards
Biomodels Manual Curation Y Domain experts curated biological connection maps and associated mathematical models
STKE Manual Curation N Repository of canonical pathways
Ingenuity Systems Manual Curation Y Commercial mammalian biological knowledgebase about genes, drugs, chemical, cellular and disease processes, and signaling and metabolic pathways
Human signaling network Manual Curation Y Literature-curated human signaling network, the largest human signaling network database
PID[permanent dead link] Manual Curation Y Compendium of several highly structured, assembled signaling pathways
BioPP Manual and Automated Curation Y Repository of biological pathways built using CellDesigner

Legend: Y – Yes, N – No; BIND – Biomolecular Interaction Network Database, DIP – Database of Interacting Proteins, GNPV – Genome Network Platform Viewer, HPRD = Human Protein Reference Database, MINT – Molecular Interaction database, MIPS – Munich Information center for Protein Sequences, UNIHI – Unified Human Interactome, OPHID – Online Predicted Human Interaction Database, EcoCyc – Encyclopaedia of E. Coli Genes and Metabolism, MetaCyc – aMetabolic Pathway database, KEGG – Kyoto Encyclopedia of Genes and Genomes, PANTHER – Protein Analysis Through Evolutionary Relationship database, STKE – Signal Transduction Knowledge Environment, PID – The Pathway Interaction Database, BioPP – Biological Pathway Publisher. A comprehensive list of resources can be found at http://www.pathguide.org.

Pathway-related databases and tools

KEGG

The increasing amount of genomic and molecular information is the basis for understanding higher-order biological systems, such as the cell and the organism, and their interactions with the environment, as well as for medical, industrial and other practical applications. The KEGG resource[109] provides a reference knowledge base for linking genomes to biological systems, categorized as building blocks in the genomic space (KEGG GENES), the chemical space (KEGG LIGAND), wiring diagrams of interaction networks and reaction networks (KEGG PATHWAY), and ontologies for pathway reconstruction (BRITE database).[110] The KEGG PATHWAY database is a collection of manually drawn pathway maps for metabolism, genetic information processing, environmental information processing such as signal transduction, ligand–receptor interaction and cell communication, various other cellular processes and human diseases, all based on extensive survey of published literature.[111]

GenMAPP

Gene Map Annotator and Pathway Profiler (

single nucleotide polymorphism (SNP), and splicing, has been implemented with GenMAPP database to support analysis of complex data. GenMAPP also offers innovative ways to display and share data by incorporating HTML export of analyses for entire sets of pathways as organized web pages.[114] In short, GenMAPP
provides a means to rapidly interrogate complex experimental data for pathway-level changes in a diverse range of organisms.

Reactome

Given the genetic makeup of an organism, the complete set of possible reactions constitutes its

hematopoeisis.[119]
In summary, Reactome provides high-quality curated summaries of fundamental biological processes in humans in a form of biologist-friendly visualization of pathways data, and is an open-source project.

Pathway-oriented approaches

In the post-genomic age, high-throughput

genomic data to the public domain. With RNA interference, it is possible to distill the inferences contained in the experimental literature and primary databases into knowledge bases that consist of annotated representations of biological pathways. In this case, individual genes and proteins are known to be involved in biological processes, components, or structures, as well as how and where gene products interact with each other.[121][122] Pathway-oriented approaches for analyzing microarray data, by grouping long lists of individual genes, proteins, and/or other biological molecules according to the pathways they are involved in into smaller sets of related genes or proteins, which reduces the complexity, have proven useful for connecting genomic data to specific biological processes and systems. Identifying active pathways that differ between two conditions can have more explanatory power than a simple list of different genes or proteins. In addition, a large number of pathway analytic methods exploit pathway knowledge in public repositories such as Gene Ontology (GO) or Kyoto Encyclopedia of Genes and Genomes (KEGG), rather than inferring pathways from molecular measurements.[123][124] Furthermore, different research focuses have given the word "pathway" different meanings. For example, 'pathway' can denote a metabolic pathway involving a sequence of enzyme-catalyzed reactions of small molecules, or a signaling pathway involving a set of protein phosphorylation reactions and gene regulation events. Therefore, the term "pathway analysis" has a very broad application. For instance, it can refer to the analysis physical interaction networks (e.g., protein–protein interactions), kinetic simulation of pathways, and steady-state pathway analysis (e.g., flux-balance analysis), as well as its usage in the inference of pathways from expression and sequence data. Several functional enrichment analysis tools[125][126][127][128] and algorithms[129] have been developed to enhance data interpretation. The existing knowledge base–driven pathway analysis methods in each generation have been summarized in recent literature.[130]

Applications of pathway analysis in medicine

Colorectal cancer (CRC)

A program package MatchMiner was used to scan HUGO names for cloned genes of interest are scanned, then are input into GoMiner, which leveraged the GO to identify the biological processes, functions and components represented in the gene profile. Also, Database for Annotation, Visualization, and Integrated Discovery (DAVID) and KEGG database can be used for the analysis of microarray expression data and the analysis of each GO biological process (P), cellular component (C), and molecular function (F) ontology. In addition, DAVID tools can be used to analyze the roles of genes in metabolic pathways and show the biological relationships between genes or gene-products and may represent metabolic pathways. These two databases also provide bioinformatics tools online to combine specific biochemical information on a certain organism and facilitate the interpretation of biological meanings for experimental data. By using a combined approach of Microarray-Bioinformatic technologies, a potential metabolic mechanism contributing to colorectal cancer (CRC) has been demonstrated[131] Several environmental factors may be involved in a series of points along the genetic pathway to CRC. These include genes associated with bile acid metabolism, glycolysis metabolism and fatty acid metabolism pathways, supporting a hypothesis that some metabolic alternations observed in colon carcinoma may occur in the development of CRC.[131]

Parkinson's disease (PD)

Cellular models are instrumental in dissecting a complex pathological process into simpler molecular events.

mitochondrial impairment and dysfunctional mitophagy, unfolded protein stress and improper removal of misfolded proteins) have been widely explored in cell lines, challenged with toxic insults or genetically modified. The central role of a-synuclein has generated many models aiming to elucidate its contribution to the dysregulation of various cellular processes. Classical cellular models appear to be the correct choice for preliminary studies on the molecular action of new drugs or potential toxins and for understanding the role of single genetic factors. Moreover, the availability of novel cellular systems, such as cybrids or induced pluripotent stem cells, offers the chance to exploit the advantages of an in vitro investigation, although mirroring more closely the cell population being affected.[132]

Alzheimer's disease (AD)

oxidative and metabolic compromise may thereby render neurons vulnerable to excitotoxicity and apoptosis. Recent studies suggest that AD can manifest systemic alterations in energy metabolism (e.g., increased insulin resistance and dysregulation of glucose metabolism). Emerging evidence that dietary restriction can forestall the development of AD is consistent with a major "metabolic" component to these disorders, and provides optimism that these devastating brain disorders of aging may be largely preventable.[133]

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External links
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