Signal transduction
From Wikipedia, the free encyclopedia
An overview of major signal transduction pathways in mammals.
Signal transduction occurs when an extracellular signaling[1] molecule activates a specific
receptor located on the cell surface or inside the cell. In turn, this receptor triggers a biochemical
chain of events inside the cell, creating a response.[2] Depending on the cell, the response alters
the cell's metabolism, shape, gene expression, or ability to divide.[3] The signal can be amplified
at any step. Thus, one signaling molecule can cause many responses.[4]
Contents



1 History
2 Environmental stimuli
3 Receptors
o 3.1 Extracellular
 3.1.1 G protein-coupled
 3.1.2 Tyrosine and histidine kinase
 3.1.3 Integrin
 3.1.4 Toll gate
 3.1.5 Ligand-gated ion channel
o 3.2 Intracellular
o
o
o
o
o





3.3 Second messengers
3.4 Calcium
3.5 Lipophilics
3.6 Nitric oxide
3.7 Redox signaling
4 Cellular responses
5 Major pathways
6 See also
7 References
8 External links
History
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.
In 1970, Martin Rodbell examined the effects of glucagon on a rat's liver cell membrane
receptor. He noted that guanosine triphosphate disassociated glucagon from this receptor and
stimulated the G-protein, which strongly influenced the cell's metabolism. Thus, he deduced that
the G-protein is a transducer that accepts glucagon molecules and affects the cell.[5] For this, he
shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G. Gilman.
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 cellsurface 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 cellsubstratum 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
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;[citation needed] many disease processes, such as
diabetes and heart disease arise from defects 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,[20] and odorants binding
to odorant receptors in the nasal epithelium.[21] 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,[22] and yeast cells use mating factors to determine the mating types of other cells and to
participate in sexual reproduction.[23]
Receptors
Receptors can be roughly divided into two major classes: intracellular receptors and extracellular
receptors.
Extracellular
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.[24] 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.
Many adaptor proteins and enzymes activated as part of signal transduction possess specialized
protein domains that bind to specific secondary messenger molecules. For example, calcium ions
bind to the EF hand domains of calmodulin, allowing it to bind and activate calmodulindependent kinase. PIP3 and other phosphoinositides do the same thing to the Pleckstrin homology
domains of proteins such as the kinase protein AKT.
G protein-coupled
Main article: G-protein-coupled receptor
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.[25] 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.[26] 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.[27] 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.
A study was conducted where a point mutation was inserted into the gene encoding the
chemokine receptor CXCR2; mutated cells underwent a malignant transformation due to the
expression of CXCR2 in an active conformation despite the absence of chemokine-binding. This
meant that chemokine receptors can contribute to cancer development.[28]
Tyrosine and histidine kinase
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.[29] To perform signal transduction, RTKs need to form dimers in the
plasma membrane;[30] 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.[29]
As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction from
the activated RTK into the cell. In this case, the G proteins are members of the Ras, Rho, and Raf
families, referred to collectively as small G proteins. They act as molecular switches usually
tethered to membranes by isoprenyl groups linked to their carboxyl ends. Upon activation, they
assign proteins to specific membrane subdomains where they participate in signaling. Activated
RTKs in turn activate small G proteins that activate guanine nucleotide exchange factors such as
SOS1. Once activated, these exchange factors can activate more small G proteins, thus
amplifying the receptor's initial signal. The mutation of certain RTK genes, as with that of
GPCRs, can result in the expression of receptors that exist in a constitutively activate state; such
mutated genes may act as oncogenes.[31]
Histidine-specific protein kinases are structurally distinct from other protein kinases and are
found in prokaryotes, fungi, and plants as part of a two-component signal transduction
mechanism: a phosphate group from ATP is first added to a histidine residue within the kinase,
then transferred to an aspartate residue on a receiver domain on a different protein or the kinase
itself, thus activating the aspartate residue.[32]
Integrin
Main article: Integrin
An overview of integrin-mediated signal transduction, adapted from Hehlgens et al. (2007).[33]
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.[33] As shown in the picture to the right, cooperative
integrin-RTK signalling determines the timing of cellular survival, apoptosis, proliferation, and
differentiation.
Important differences exist between integrin-signalling in circulating blood cells and noncirculating cells such as epithelial cells; integrins of circulating cells are normally inactive. For
example, cell membrane integrins on circulating leukocytes are maintained in an inactive state to
avoid epithelial cell attachment; they are activated only in response to stimuli such as those
received at the site of an inflammatory response. In a similar manner, integrins at the cell
membrane of circulating platelets are normally kept inactive to avoid thrombosis. Epithelial cells
(which are non-circulating) normally have active integrins at their cell membrane, helping
maintain their stable adhesion to underlying stromal cells that provide signals to maintain normal
functioning.[34]
Toll gate
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.[35][36][37] 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
Main article: Ligand-gated ion channel
A ligand-gated ion channel, upon binding with a ligand, changes conformation to open a channel
in the cell membrane through which ions relaying signals can pass. An example of this
mechanism is found in the receiving cell of a neural synapse. The influx of ions that occurs in
response to the opening of these channels induces action potentials, such as those that travel
along nerves, by depolarizing the membrane of post-synaptic cells, resulting in the opening of
voltage-gated ion channels.
An example of an ion allowed into the cell during a ligand-gated ion channel opening is Ca2+; it
acts as a second messenger initiating signal transduction cascades and altering the physiology of
the responding cell. This results in amplification of the synapse response between synaptic cells
by remodelling the dendritic spines involved in the synapse.
Intracellular
Main article: Intracellular receptor
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.
Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element
(HRE) sequences, located in the promoter region of the genes activated by the hormone-receptor
complex. Due to their enabling gene transcription, they are alternatively called inductors of gene
expression. All hormones that act by regulation of gene expression have two consequences in
their mechanism of action; their effects are produced after a characteristically long period of time
and their effects persist for another long period of time, even after their concentration has been
reduced to zero, due to a relatively slow turnover of most enzymes and proteins that would either
deactivate or terminate ligand binding onto the receptor.
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.
Retinoic acid receptors are another subset of nuclear receptors. They can be activated by an
endocrine-synthesized ligand that entered the cell by diffusion, a ligand synthesised from a
precursor like retinol brought to the cell through the bloodstream or a completely intracellularly
synthesised ligand like prostaglandin. These receptors are located in the nucleus and are not
accompanied by HSPs; they repress their gene by binding to their specific DNA sequence when
no ligand binds to them, and vice versa.
Certain intracellular receptors of the immune system are cytoplasmic receptors; recently
identified NOD-like receptors (NLRs) reside in the cytoplasm of some eukaryotic cells and
interact with ligands using a leucine-rich repeat (LRR) motif similar to TLRs. Some of these
molecules like NOD2 interact with RIP2 kinase that activates NF-κB signaling, whereas others
like NALP3 interact with inflammatory caspases and initiate processing of particular cytokines
like interleukin-1β.[38][39]
Second messengers
First messengers are the intercellular chemical messengers (hormones, neurotransmitters, and
paracrine/autocrine agents) that reach the cell from the extracellular fluid and bind to their
specific receptors. Second messengers are the substances that enter the cytoplasm and act within
the cell to trigger a response. In essence, second messengers serve as chemical relays from the
plasma membrane to the cytoplasm, thus carrying out intracellular signal transduction.
Calcium
The release of calcium ions from the endoplasmic reticulum into the cytosol results in its binding
to signaling proteins that are then activated; it is then sequestered in the smooth endoplasmic
reticulum and the mitochondria. Two combined receptor/ion channel proteins control the
transport of calcium: the InsP3-receptor that transports calcium upon interaction with inositol
triphosphate on its cytosolic side; and the ryanodine receptor named after the alkaloid ryanodine,
similar to the InsP3 receptor but having a feedback mechanism that releases more calcium upon
binding with it. The nature of calcium in the cytosol means that it is active for only a very short
time, meaning its free state concentration is very low and is mostly bound to organelle molecules
like calreticulin when inactive.
Calcium is used in many processes including muscle contraction, neurotransmitter release from
nerve endings, and cell migration. The three main pathways that lead to its activation are GPCR
pathways, RTK pathways, and gated ion channels; it regulates proteins either directly or by
binding to an enzyme.
Lipophilics
Lipophilic second messenger molecules are derived from lipids residing in cellular membranes;
enzymes stimulated by activated receptors activate the lipids by modifying them. Examples
include diacylglycerol and ceramide, the former required for the activation of protein kinase C.
Nitric oxide
Nitric oxide (NO) acts as a second messenger because it is a free radical that can diffuse through
the plasma membrane and affect nearby cells. It is synthesised from arginine and oxygen by the
NO synthase and works through activation of soluble guanylyl cyclase, which when activated
produces another second messenger, cGMP. NO can also act through covalent modification of
proteins or their metal co-factors; some have a redox mechanism and are reversible. It is toxic in
high concentrations and causes damage during stroke, but is the cause of many other functions
like relaxation of blood vessels, apoptosis, and penile erections.
Redox signaling
In addition to nitric oxide, other electronically activated species are also signal-transducing
agents in a process called redox signaling. Examples include superoxide, hydrogen peroxide,
carbon monoxide, and hydrogen sulfide. Redox signaling also includes active modulation of
electronic flows in semiconductive biological macromolecules.[40]
Cellular responses
Gene activations[41] and metabolism alterations[42] 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[42] 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.[43]
Mammalian cells require stimulation for cell division and survival; in the absence of growth
factor, apoptosis ensues. Such requirements for extracellular stimulation are necessary for
controlling cell behavior in unicellular and multicellular organisms; signal transduction pathways
are perceived to be so central to biological processes that a large number of diseases are
attributed to their disregulation. Three basic signals determine cellular growth:



Stimulatory (growth factors)
o 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))
o Transcription independent response
For example epidermal growth factor (EGF) binds the epidermal growth factor
receptor (EGFR), which causes dimerization and autophosphorylation of the
EGFR, which in turn activates the intracellular signaling pathway .[44]
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
Following are some major signaling pathways, demonstrating how ligands binding to their
receptors can affect second messengers and eventually result in altered cellular responses.

MAPK/ERK pathway: A pathway that couples intracellular responses to the binding of
growth factors to cell surface receptors. This pathway is very complex and includes
many protein components.[45] In many cell types, activation of this pathway promotes cell
division, and many forms of cancer are associated with aberrations in it.[46]

cAMP-dependent pathway: In humans, cAMP works by activating protein kinase A
(PKA, cAMP-dependent protein kinase) (see picture), and, thus, further effects depend
mainly on cAMP-dependent protein kinase, which vary based on the type of cell.

IP3/DAG pathway: PLC cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate
(PIP2) yielding diacyl glycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG
remains bound to the membrane, and IP3 is released as a soluble structure into the
cytosol. IP3 then diffuses through the cytosol to bind to IP3 receptors, particular calcium
channels in the endoplasmic reticulum (ER). These channels are specific to calcium and
allow the passage of only calcium to move through. This causes the cytosolic
concentration of Calcium to increase, causing a cascade of intracellular changes and
activity.[47] In addition, calcium and DAG together works to activate PKC, which goes on
to phosphorylate other molecules, leading to altered cellular activity. End-effects include
taste, manic depression, tumor promotion, etc.[47]
See also
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DNA damage checkpoints
Functional selectivity
GTPases
Hormones as signals
Protein phosphatase
Redox signaling
Transduction
Two-component regulatory system
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