Signal transduction

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An overview of major signal transduction pathways in mammals.



Occurrence of the term signal transduction in papers since 1977. These figures were derived by an analysis of the papers contained within the MEDLINE database.


The earliest MEDLINE entry for "signal transduction" dates from 1972.[6] Some early articles used the terms signal transmission and sensory transduction.[7][8] In 2007, a total of 48,377 scientific papers—including 11,211 review papers—were published on the subject. The term first appeared in a paper's title in 1979.[9][10] Widespread use of the term has been traced to a 1980 review article by Rodbell:[5][11] Research papers focusing on signal transduction first appeared in large numbers in the late 1980s and early 1990s.[12]

Signal transduction involves the binding of extracellular signalling molecules and ligands to cell-surface receptors that trigger events inside the cell. The combination of messenger with receptor causes a change in the conformation of the receptor, known as receptor activation. This activation is always the initial step (the cause) leading to the cell's ultimate responses (effect) to the messenger. Despite the myriad of these ultimate responses, they are all directly due to changes in particular cell proteins. Intracellular signaling cascades can be started through cell-substratum interactions; examples are the integrin that binds ligands in the extracellular matrix and steroids.[13] Most steroid hormones have receptors within the cytoplasm and act by stimulating the binding of their receptors to the promoter region of steroid-responsive genes.[14] Examples of signaling molecules include the hormone melatonin,[15] the neurotransmitter acetylcholine[16] and the cytokine interferon γ.[17]

The classifications of signalling molecules do not take into account the molecular nature of each class member; neurotransmitters range in size from small molecules such as dopamine[18] to neuropeptides such as endorphins.[19] Some molecules may fit into more than one class; for example, epinephrine is a neurotransmitter when secreted by the central nervous system and a hormone when secreted by the adrenal medulla.

Environmental stimuli[edit]

With single-celled organisms, the variety of signal transduction processes influence its reaction to its environment.[citation needed] With multicellular organisms, numerous processes are required for coordinating individual cells to support the organism as a whole; the complexity of these processes tend to increase with the complexity of the organism.[citation needed] Sensing of environments at the cellular level relies on signal transduction; modeling signal transduction systems as self-organizing allows to explain how equilibria are maintained,[20] many disease processes, such as diabetes and heart disease arise from defects or dysregulations in these pathways, highlighting the importance of this process in biology and medicine.

Various environmental stimuli exist that initiate signal transmission processes in multicellular organisms; examples include photons hitting cells in the retina of the eye,[21] and odorants binding to odorant receptors in the nasal epithelium.[22] Certain microbial molecules, such as viral nucleotides and protein antigens, can elicit an immune system response against invading pathogens mediated by signal transduction processes. This may occur independent of signal transduction stimulation by other molecules, as is the case for the toll-like receptor. It may occur with help from stimulatory molecules located at the cell surface of other cells, as with T-cell receptor signaling. Unicellular organisms may respond to environmental stimuli through the activation of signal transduction pathways. For example, slime molds secrete cyclic adenosine monophosphate upon starvation, stimulating individual cells in the immediate environment to aggregate,[23] and yeast cells use mating factors to determine the mating types of other cells and to participate in sexual reproduction.[24]




Extracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside; the molecule does not pass through the membrane. This binding stimulates a series of events inside the cell; different types of receptors stimulate different responses and receptors typically respond to only the binding of a specific ligand. Upon binding, the ligand induces a change in the conformation of the inside part of the receptor.[25] These result in either the activation of an enzyme in the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm.

In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity; examples include tyrosine kinase and phosphatases. Some of them create second messengers such as cyclic AMP and IP3, the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated proteins interact with adaptor proteins that facilitate signalling protein interactions and coordination of signalling complexes necessary to respond to a particular stimulus. Enzymes and adaptor proteins are both responsive to various second messenger molecules.


G protein-coupled[edit]

G protein-coupled receptors (GPCRs) are a family of integral transmembrane proteins that possess seven transmembrane domains and are linked to a heterotrimeric G protein. Many receptors are in this family, including adrenergic receptors and chemokine receptors.

Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor; it exists as a heterotrimer consisting of Gα, Gβ, and Gγ.[26] Once the GPCR recognizes a ligand, the conformation of the receptor changes to activate the G protein, causing Gα to bind a molecule of GTP and dissociate from the other two G-protein subunits. The dissociation exposes sites on the subunits that can interact with other molecules.[27] The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins such as phospholipases and ion channels, the latter permitting the release of second messenger molecules.[28] The total strength of signal amplification by a GPCR is determined by the lifetimes of the ligand-receptor complex and receptor-effector protein complex and the deactivation time of the activated receptor and effectors through intrinsic enzymatic activity.


Tyrosine and histidine kinase[edit]

Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellular kinase domain and an extracellular domain that binds ligands; examples include growth factor receptors such as the insulin receptor.[30] To perform signal transduction, RTKs need to form dimers in the plasma membrane;[31] the dimer is stabilized by ligands binding to the receptor. The interaction between the cytoplasmic domains stimulates the autophosphorylation of tyrosines within the domains of the RTKs, causing conformational changes. Subsequent to this, the receptors' kinase domains are activated, initiating phosphorylation signaling cascades of downstream cytoplasmic molecules that facilitate various cellular processes such as cell differentiation and metabolism.[30]




Main article: Integrin
An overview of integrin-mediated signal transduction, adapted from Hehlgens et al. (2007).[34]

Integrins are produced by a wide variety of cells; they play a role in cell attachment to other cells and the extracellular matrix and in the transduction of signals from extracellular matrix components such as fibronectin and collagen. Ligand binding to the extracellular domain of integrins changes the protein's conformation, clustering it at the cell membrane to initiate signal transduction. Integrins lack kinase activity; hence, integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules, the main coordinator being integrin-linked kinase.[34] As shown in the picture to the right, cooperative integrin-RTK signalling determines the timing of cellular survival, apoptosis, proliferation, and differentiation.


Toll gate[edit]

Main article: Toll-like receptor

When activated, toll-like receptors (TLRs) take adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adaptor molecules are known to be involved in signaling, which are Myd88, TIRAP, TRIF, and TRAM.[36][37][38] These adapters activate other intracellular molecules such as IRAK1, IRAK4, TBK1[disambiguation needed], and IKKi that amplify the signal, eventually leading to the induction or suppression of genes that cause certain responses. Thousands of genes are activated by TLR signaling, implying that this method constitutes an important gateway for gene modulation.

Ligand-gated ion channel[edit]




Intracellular receptors, such as nuclear receptors and cytoplasmic receptors, are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are lipophilic hormones like the steroid hormones testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the nuclear membrane into the nucleus, enabling gene transcription and protein production.


Signal transduction via these receptors involves little proteins, but the details of gene regulation by this method are not well-understood. Nucleic receptors have DNA-binding domains containing zinc fingers and a ligand-binding domain; the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the receptor are usually hexameric repeats of any kind; the sequences are similar but their orientation and distance differentiate them. The ligand-binding domain is additionally responsible for dimerization of nucleic receptors prior to binding and providing structures for transactivation used for communication with the translational apparatus.

Steroid receptors are a subclass of nuclear receptors located primarily within the cytosol; in the absence of steroids, they cling together in an aporeceptor complex containing chaperone or heatshock proteins (HSPs). The HSPs are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence enabling its passage into the nucleus is accessible. Steroid receptors, on the other hand, may be repressive on gene expression when their transactivation domain is hidden; activity can be enhanced by phosphorylation of serine residues at their N-terminal as a result of another signal transduction pathway, a process called crosstalk.



Second messengers[edit]







Nitric oxide[edit]


Redox signaling[edit]


Cellular responses[edit]

Gene activations[42] and metabolism alterations[43] are examples of cellular responses to extracellular stimulation that require signal transduction. Gene activation leads to further cellular effects, since the products of responding genes include instigators of activation; transcription factors produced as a result of a signal transduction cascade can activate even more genes. Hence, an initial stimulus can trigger the expression of a large number of genes, leading to physiological events like the increased uptake of glucose from the blood stream[43] and the migration of neutrophils to sites of infection. The set of genes and their activation order to certain stimuli is referred to as a genetic program.[44]


  • Stimulatory (growth factors)
    • Transcription dependent response
      For example steroids act directly as transcription factor (gives slow response, as transcription factor must bind DNA, which needs to be transcribed. Produced mRNA needs to be translated, and the produced protein/peptide can undergo Posttranslational_modification (PMT))
    • Transcription independent response
  • Inhibitory (cell-cell contact)
  • Permissive (cell-matrix interactions)

The combination of these signals are integrated in an altered cytoplasmic machinery which leads to altered cell behaviour.

Major pathways[edit]


See also[edit]


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