Cell signaling and communication

Akshata
Some concepts that are easy to be confused:

• Now, there are many terms about cell communication used in cell biology, especially to the cell biology
of tumor. But, some of them are easy to be confused. I define them as the follows:
• Cell signaling: Cells release some signal out to some cells else.
• Cell communication: The signal from a cell is transmitted to another cell by some transmitter, and causes
a specific reaction.
• Cell recognition: A cell interacts with another cell by the signal molecules located on cell surface, and
causes specific response of another cell.
• Signal transduction: The signals from out side of cell (Light, electricity, and molecules) are received by the
receptors located on cell surface, cause the change of intracellular signal level, and start a serial
responses of cell.
Signal molecules
• Signals can be chemical signals or physical signals. Chemical signal is much more important than physical signal in
cell biology.
• Chemical signals include oligopeptides, proteins, gas molecules (NO、CO), amino acids, nucleotides, lipids,
cholesterol, and others.
• The characters of chemical signals are
① specificity
② efficiency. One or more molecules can cause a strong response because the signal transduction system can
enlarge the signal stimulation they can be inactivated after the signal transmission.
• By the routes of generation and role, the chemical signal molecules can be sorted as 4 types: hormones, neuron
transmitters, local mediated factors, and gas molecules.
• By the solubility, the signal molecules can be sorted as two types: lipid soluble and water soluble molecules. Lipid
soluble signal, such as some hormone, can be transported into cell directly passing through the bilayers
membrane.
• Water soluble signal molecule, such as neuron transmitters, can not pass through the bilayers membrane. They
have to bind to their receptors and exchange the signal type, transfer the information to the intracellular signal
(cAMP) or activate the kinase for receptor to result in cell responses.
• So, these signal molecules are called as primary messenger, and intracellular signal molecules (cAMP, cGMP, IP3
and DG) as secondary messenger.
• Ca2+ can be named as third messenger because its signal transmission is depended on secondary messenger.
• Secondary messenger can enlarge the signal function.
Receptors:

• Receptor can selectively bind to its ligand (Signal molecules). Receptor is glycoprotein usually
composed of two function domains at least (ligand binding part and activating part).
• The features of the interaction between ligand and receptor are:
① specificity
② saturated limit
③ high affinity.
• The response of cell to a signal depends on both receptor and cell type. Same signal can cause
different responses on different cells. For example, Ach can cause the contraction of skeleton muscle,
inhibit the contraction rate of heart muscle, and cause the secretion of saliva
• Different signal can cause same responses also. For example, both adrenalin and pancreatic glucagon
can enhance the level of blood sugar.
• If some signal stimulates cell consistently, cell can make its receptor obtuse by the ways as following:
① modify and inactivate receptor. ② move the receptor into inside of cell (receptor sequestration).
③ By endocytosis, digest receptor with lysosome (receptor down-regulation).
• Cells in a multicellular organisms communicate by chemical messengers
• Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells
• In local signaling, animal cells may communicate by direct contact
• In many other cases, animal cells communicate using local regulators, messenger molecules that travel only
short distances
• In long-distance signaling, plants and animals use chemicals called hormones

Plasma membranes

Gap junctions
Plasmodesmata
between animal cells
between plant cells

Cell junctions

Cell-cell
Types of Signaling

1. Direct cell-cell or cell-matrix (integrins and cadherins)

2. Indirect: Secreted molecules or extracellular signaling can occur over :
a. large distances or endocrine signaling – signaling molecules are called hormones
• act on target cells distant from their site of synthesis
• usually carried through the bloodstream
b. short distances or paracrine signaling – affects target cells within proximity to
the cell that synthesized the molecule
• usually mediated by neurotransmitters and some growth factors
• no distance or autocrine signaling – the signal feeds-back and affects itself
• action of many growth factors
• these compounds generally act on themselves to regulate proliferation
• seen frequently in tumor cells

• many compounds can act through two or even three types of cell signaling
e.g. growth factors (e.g. EGF) – paracrine and autocrine and
endocrine
-epinephrine – endocrine and paracrine
The Three Stages of Cell Signaling

• Earl W. Sutherland discovered how the hormone epinephrine acts on cells and
suggested that cells receiving signals went through 3 processes:
1. Reception of extracellular signal by cell

2. Transduction of signal from outside of cell to inside of cell—often

multi-stepped

3. Response cellular response is inititiated and/or occurs entirely within

receiving cell
EXTRACELLULAR CYTOPLASM
FLUID
Plasma membrane

Reception Transduction Response

Receptor

Activation
of cellular
response
Relay molecules in a signal transduction
pathway

Signal
molecule
 1. Reception

Three Stages
2a. Transduction

2b. Transduction

2c. Transduction

2d. Transduction

3. Response

Responses usually involve increasing or decreasing some Protein’s

Reception: A signal molecule binds to a receptor protein,
causing it to change shape

• The binding between a signal molecule (ligand) and receptor is highly

specific
•A conformational change in a receptor is often the initial transduction of
the signal
•Most signal receptors are plasma membrane proteins
Intracellular Receptors
► Some receptor proteins are intracellular, found in the cytosol or nucleus of target cells
► Small or hydrophobic chemical messengers can readily cross the membrane and activate
receptors
► Examples of hydrophobic messengers are the steroid and thyroid hormones of animals
► An activated hormone-receptor complex can act as a transcription factor, turning on specific
genes
 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

External environment Cytoplasm

Signal Cellular
transduction response
pathway

Membrane receptor

Signal Cellular
transduction response
Hydrophilic
pathway
ligand

Intracellular receptor

Hydrophobic
ligand
Plasma membrane
Receptors in the Plasma Membrane

► Most water-soluble signal molecules bind to specific sites on receptor proteins in the plasma
membrane
► There are three main types of membrane receptors:
► G-protein-linked receptors
► Receptor tyrosine kinases
► Ion channel receptors
 G-protein-linked receptor:

Trimeric GTP-binding regulatory protein is called as G protein located on plasma side of membrane. G
protein is composed of subunit α, β, and γ. G protein is a switch during the signal transduction that can shut
down when subunit α binds to GDP, opened up when subunit α binds to GTP. Subunit α is of GTPase activity
that can hydrolyze GTP.

G-protein-linked receptor is seven-times-transmembrane protein. The extracellular part of the receptor

recognizes and bind signal molecule, and intracellular part of the receptor links to G protein. The extracellular
signal bind to the receptor can cause the second messenger formed inside cell by the linked G protein.

The receptors for neuron transmitters, peptide hormones are the G-protein-linked receptor. The receptors
for the physical and chemical excitations of taste sense and visual sense are G-protein-linked receptors too.

The signal ways mediated by G-protein-linked receptor include cAMP signal way and phosphatidylinositol
signal way.
 Receptor tyrosine kinases
• Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines
• A receptor tyrosine kinase can trigger multiple signal transduction pathways at once
• A kinase, alternatively known as a phosphotransferase, is a type of enzyme that transfers
phosphate groups from high-energy donor molecules, such as ATP, to specific substrates. The
process is referred to as phosphorylation.
Signal Signal-binding site
molecule
α Helix in the Signal
membrane molecule

Tyr Tyr
Tyrosines Tyr Tyr Tyr Tyr
Tyr Tyr
Tyr Tyr Tyr Tyr
Tyr Tyr
Tyr Tyr Tyr Tyr

Receptor tyrosine
kinase proteins Dimer
CYTOPLASM (inactive monomers)

Activated relay
proteins

Cellular
Tyr Tyr P Tyr Tyr P P Tyr Tyr P response 1
Tyr Tyr P Tyr Tyr P Tyr Tyr P
P
Tyr Tyr P Tyr Tyr P P Tyr Tyr P Cellular
6 ATP 6 ADP response 2

Activated tyrosine- Fully activated receptor

kinase regions tyrosine-kinase
(unphosphorylated (phosphorylated Inactive
dimer) dimer) relay proteins
Ion-channel-linked receptor Signal
molecule
(ligand)
Gate
closed Ions

• An ion channel receptor acts as a gate when the receptor changes Ligand-gated
Plasma
membrane
shape ion channel receptor

• When a signal molecule binds as a ligand to the receptor, the gate

allows specific ions, such as Na+ or Ca2+, through a channel in the Gate open

receptor

Cellular
response

Gate closed
Transduction: Cascades of molecular interactions relay signals from
receptors to target molecules in the cell

• Transduction usually involves multiple steps

• Multistep pathways can amplify a signal: A few molecules can produce a large cellular
response
• Multistep pathways provide more opportunities for coordination and regulation
• The molecules that relay a signal from receptor to response are mostly proteins
• The receptor activates another protein, which activates another, and so on, until the
protein producing the response is activated
• At each step, the signal is transduced into a different form, usually a conformational
change
Protein Phosphorylation and Dephosphorylation

• In many pathways, the signal is transmitted by a cascade of protein phosphorylations

• Phosphatase enzymes remove the phosphates
• This phosphorylation (kinases) and dephosphorylation (phosphatases) system acts as a
molecular switch, turning activities on and off
 Signal molecule

Receptor
Activated relay
molecule

Inactive
protein kinase
1 Active
protein
kinase
1

Ph
os
Inactive

ph
protein kinase ATP

or
ADP Active P
2

yla
protein

tio
kinase

n
PP

ca
Pi 2

sc
ad
Inactive

e
protein kinase ATP
ADP Active P
3
protein
PP kinase
Pi 3

Inactive
protein ATP
ADP P
Active Cellular
PP protein response
Pi
Small Molecules and Ions as Second Messengers

• Second messengers are small, nonprotein, water-soluble molecules or ions

• The extracellular signal molecule that binds to the membrane is a pathway’s “first
messenger”
• Second messengers can readily spread throughout cells by diffusion
• Second messengers participate in pathways initiated by G-protein-linked receptors and
receptor tyrosine kinases
Cyclic AMP

• Cyclic AMP (cAMP) is one of the most widely used second messengers
• Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to
an extracellular signal
• Many signal molecules trigger formation of cAMP
• Other components of cAMP pathways are G proteins, G-protein-linked receptors, and protein
kinases
• cAMP usually activates protein kinase A, which phosphorylates various other proteins
• Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl
cyclase
 First messenger
(signal molecule
such as epinephrine)
Adenylyl
G protein cyclase

G-protein-linked GTP
receptor

ATP
Second
cAMP messenger

Protein
kinase A

Cellular responses
Calcium ions and Inositol Triphosphate (IP3)
• In the phosphotidylinositol signal way, extracellular signal molecules combine to the G
protein linked receptor on membrane surface, and activate the phospholipase C (PLC-β)
that hydrolyze 4,5-diphophotidylinositol (PIP2) into 1,4,5–triphophotidylinositol (inositol
phosphate 3, IP3) and diacyl glycerol (DG) as two second messengers. Extracellular signals
are exchanged as intracellular signals at this time. We call the signal system as double
messenger system).
• IP3 can combine to the IP3 ligand gate Ca2+ channel to open it, and the Ca2+ concentration
in cell will be lifted up. The high Ca2+ concentration will activate every Ca2+ dependent
protein. If you use Ca2+ carrier ionomycin to treat cultured cells, you will get same result as
described above.
• DAG can activate plasma membrane bound protein kinase C (PKC). PKC is distributed in
cell plasma without activity usually, but when cell received some excitation, IP3 will make
high Ca2+ concentration, then, PKC is translocated onto plasma membrane inside surface to
be activated by DAG. The activated PKC can phosphorate Ser/Thr residues of proteins causing
different cell exhibited with different response. For examples, secretion of cell, contraction of
muscle, proliferation and differentiation of cell.
•
Cytoplasmic and Nuclear Responses

• Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities
• The response may occur in the cytoplasm or may involve action in the nucleus
• Many pathways regulate the activity of enzymes
• Many other signaling pathways regulate the synthesis of enzymes or other proteins, usually
by turning genes on or off in the nucleus
• The final activated molecule may function as a transcription factor
Fine-Tuning of the Response

• Multistep pathways have two important benefits:

• Amplifying the signal (and thus the response)
• Contributing to the specificity of the response
Signal amplification
• Enzyme cascades amplify
the cell’s response
• At each step, the number of
activated products is much
greater than in the
preceding step
The Specificity of Cell Signaling

• Different kinds of cells have different collections of proteins

• These differences in proteins give each kind of cell specificity in detecting and responding to
signals
• The response of a cell to a signal depends on the cell’s particular collection of proteins
• Pathway branching and “cross-talk” further help the cell coordinate incoming signals
 Signal
molecule

Receptor

Relay
molecules

Response 1 Response 2 Response 3

Cell A. Pathway leads Cell B. Pathway branches,

to a single response leading to two responses

Activation
or inhibition

Response 4 Response 5

Cell C. Cross-talk occurs Cell D. Different receptor

between two pathways leads to a different response
SIGNALING PATHWAY

1. The Notch Signaling Pathway

2. The Hedgehog Signaling Pathway
3. Wnt
4. NF-kB
 The Hedgehog Signaling Pathway
• The Hedgehog pathway was discovered in fruit fly (Drosophila) and is conserved in
vertebrates (including humans)1,2
• The Hedgehog pathway is involved in cell growth and differentiation to control organ
formation during embryonic development
• Hedgehog signalling regulates embryonic development, ensuring that tissues reach their correct size
and location, maintaining tissue polarity and cellular content2
• In the skin, the Hedgehog pathway is critical for regulating hair follicle and sebaceous gland
development3
• Germline mutations in components of the Hedgehog signalling pathway results in a number of
developmental abnormalities4,5
• Hedgehog signalling normally remains inactive in most adult tissues2
Key components involved in Hedgehog signalling
 The Hedgehog Signaling Pathway

Receptor
•Patched (Ptc) — a 12-pass transmembrane protein embedded in the plasma
membrane.
Ligands
•Secreted hedgehog proteins (Hh) that diffuse to their targets. Mammals have
three hedgehog genes encoding three different proteins. However, hedgehog
was first identified in Drosophila, and the bristly phenotype produced by
mutations in the gene gave rise to the name.
Mechanism
• In mammals, when there is no hedgehog protein present, the patched receptors bind a second
transmembrane protein called smoothened (Smo).
• However, when Hh protein binds to patched, the Smo protein separates from Ptc
• enabling Smo to activate a zinc-finger transcription factor designated GLI.
• GLI migrates into the nucleus when it activates a variety of target genes.
• Hedgehog signaling plays many important developmental roles in the animal kingdom.
• For example,wing development in Drosophila;
• development of the brain, GI tract, fingers and toes in mammals;
• Mutations or other sorts of regulatory errors in the hedgehog pathway are associated with a number of
birth defects as well as some cancers. Basal-cell carcinoma, the most common skin cancer (and, in fact, the
most common of all cancers in much of the world), usually has mutations causing
• extra-high hedgehog or
• suppressed patched activity (both leading to elevated GLI activity).
 When the Hedgehog pathway is inactive
Patched inhibits Smoothened activity

•
No Hh ligand

No SMO-enabled
signal transduction

Inhib
ition

No intracellular
signal transduction
In the absence of Hh ligand,
PTCH inhibits SMO and the
Hedgehog signalling pathway
is suppressed
When Hedgehog ligand activates the Hedgehog pathway the
cell responds by activating expression of Hh target genes

Activation of the pathway is

initiated by Hh ligand binding to
PTCH, eventually resulting in Target gene expression
target gene expression
 The Notch Signaling Pathway
• This pathway is found throughout the animal kingdom. It differs from many of the other signaling
pathways discussed here in that the ligands as well as their receptors are transmembrane
proteins embedded in the plasma membrane of cells. Thus, signaling in this pathway requires direct
cell-to-cell contact.
Receptors
• Notch proteins are single-pass transmembrane glycoproteins. They are encoded by four genes in
vertebrates. However, the first notch gene was discovered in Drosophila where its mutation produced
notches in the wings.
Ligands
• Their ligands are also single-pass transmembrane proteins. There are many of them and often several
versions within a family (such as the serrate and delta protein families).
Mechanism
• When a cell bearing the ligand comes in contact with a cell displaying the notch receptor, the
external portion of notch is cleaved away from the cell surface (and engulfed by the
ligand-bearing cell by endocytosis). The internal portion of the notch receptor is cut away from
the interior of the plasma membrane and travels into the nucleus where it activates transcription
factors that turn the appropriate genes on (and off).
• It would appear that proper development of virtually all organs (e.g., brain, immune system,
pancreas, GI tract, heart, blood vessels, mammary glands) depends on notch signaling. Notch
signaling appears to be a mechanism by which one cell tells an adjacent cell which path of
differentiation to take (or not take).
• Defects in notch signaling have been implicated in some cancers, e.g. melanoma.
The processing and activation of Notch by
proteolytic cleavage

Inhibit neural differentiation

Wnt signaling pathway

• “Wnt” is a combination of Wg (wingless) gene in Drosophila and Int gene in MMTV, two
homologous genes
• Wnt are secreted proteins
• 19 Wnt genes in humans and mice
• Wnt proteins released from or presented on the surface of signaling cells act on target cells by
binding to Frizzled (Fz)/LDL-related protein (LDR) complex at the cell surface.
• Receptors
• Frizzled receptors, like GPCRs, are transmembrane proteins that span 7 times the plasma membrane.
• Their ligand-binding site is exposed outside the surface of the cell.
• Their effector site extends into the cytosol.
 Wnt Receptors
► Receptor tyrosine kinase
► Derailed/RYK
► ROR
► Frizzled-transmembrane receptor
► LRP (lipoprotein-receptor related
protein)
► Single-pass Tm proteins
► Cytoplasmic tail phosphorylated
by GSK3 and CK1γ
• Schematic representation of the canonical Wnt/b-catenin signaling pathway in its inactive state.
• In the absence of Wnt signal, b-catenin is recruited into the APC/Axin/GSK3b complex, and phosphorylated
by GSK3b at the N-terminal ‘destruction box’. Negative regulators, such as Dkks, WIF and FRP, inhibit the
interactions between Wnt ligands and their receptors.
• The phosphorylated b-catenin binds to b-Trcp of the proteosome machinery and is targeted for
degradation.
• As the result, no free b-catenin enters nucleus to form transcriptional complex with LEF/TCF and to
regulate downstream gene expression.
• Schematic representation of the canonical Wnt/b-catenin signaling pathway in its active state.
• Wnt binds to its Frizzled receptor and LRP5/6 co-receptor and activates Disheveled, leading to the
inhibition of APC/Axin/GSK3b-mediated b-catenin degradation.
• Stabilized b-catenin forms a transcriptional complex with LEF/TCF.
• The LEF/TCF transcriptional complex activates downstream targets such as c-Myc.
• There is crosstalk between Wnts and other signaling pathways, such as growth factors that activate
receptor tyrosine kinases.
Role of Wnt signaling

• Development
• Neural development: CNS
• Neural crest
• Limb
• Tumor formation
• Cellular growth and proliferation
 The NF-ĸB/Rel family
• NF-κB signal pathway:

• NF-κB is the transcription factor of Rel family. NF-κB is involved with the regulation of immunology,
inflammation, and the transcription of the genes that are associated with cell differentiation. In the
cells of mammalian, there are 5 NF-κB members of Rel family: RelA (P65), RelB, RelC, NF-κB1(P50), and
NF-κB2 (P52). Usually, the dimer of NF-κB is combined with IκB, an inhibition protein, to be embedded
in plasma. Extracellular excitation can promote the IκB degeneration and push NF–κB dimer to enter
nucleus for the regulation of gene transcription.

• The members of IκB family include IκBα, IκBβ, IκBγ, IκBδ, IκBε, and Bcl-3.

• IKK (IκB kinase) is the key kinase for NF-κB signal transduction. The extracellular signals, such as
TNFα and IL-1, can activate IKK to cause IκB phosphorylation. The phosphorated IkB is easy to be
degenerated.
SIGNALING THROUGH ENZYME-LINKED
CELL-SURFACE RECEPTORS

Six classes:

1. Receptor tyrosine kinases

2. Tyrosine kinase-associated receptors
3. Receptorlike tyrosine phosphatases
4. Receptor serine/threonine kinases
5. Receptor guanylyl cyclases
6. Histidine-kinase-associated receptors
 Integrating Cells into Tissues:
Cell-Cell Adhesion and Communication
• A key event in the evolution of multicellularity is the ability for cells to adhere to one another and be
able to communicate with each other evolved a series of cell-adhesion molecules or CAMs that allow
interaction with each other and with the surrounding extracellular matrix (ECM) this results in
coordinated functioning of tissues

HOW??
• These interactions result in the activation of specific signal transduction cascades eventually resulting
in the desired cellular effect
• therefore the physical interaction of CAMs with the ECM can turn pathways on or off – cellular effect
e.g. cellular interactions with the adhesion protein β1-integrin can result in activation of the
MAPK cascade
various classes of CAMs found on cells
1. cadherins – cell-cell adhesion
calcium dependent
e.g, E-cadherin, P-cadherin
2. Ig superfamily of CAMs – cell-cell adhesion
e.g. N-CAM, V-CAM
calcium-independent
some are found enriched on specific cell types –
N-CAM
3. Integrins – major cell-matrix adhesion molecule
e.g. α1 integrin, β1 integrin
 Cell-Cell adhesion: Cadherin-containing junctions
1.adherens junction – continuous band of
cadherins found in epithelial cells
connects cells tightly and interact
with the actin portion of the cytoskeleton
2.desmosomes – also found in high #s in
epithelial tissues
cells attach via cadherins – connect
to protein “plaques” that attach to the
plasma membrane and to intermediate
filaments within the cytoskeleton

cadherins are a family of calcium-dependent

CAMs
major molecules of cell-cell adhesion (homophilic)
over 40 different are known
e.g. E or epithelial cadherin
N or neural cadherin
tissues have specialized junctions made of cadherins
Cell Matrix

•three components to the ECM

• insoluble collagens – structural framework of the ECM, provides strength and resiliency
• proteoglycans – cushions cells
• adhesive matrix proteins – bind these components to receptors on the cell surface
• different combinations result in unique ECM compositions which can directly affect the activity
of the cells
• the interaction of ECM components with specific CAMs (i.e. ECM receptors) can turn certain
signaling paths ON or OFF
• also the ECM is capable of sequestering growth factors and hormones by binding them and
making them unavailable to turn cellular signaling on or off.
 Cell-matrix interactions: integrins
• Normal cells cannot grow in suspension (as cancer cells do), but need
to attach to a surface that resembles the extracellular matrix (ECM) in
a tissue.
• Cells have transmembrane proteins called integrins that anchor them
to materials in the ECM (fibronectin, collagen, proteoglycans, etc).
• Interaction of integrins with an extracellular ligand generates a variety
of signals, some essential for cell growth and differentiation.
• integrins allow connection between the extracellular matrix with the
cytoskeleton of the cell also can mediate cell-cell interactions (weak)
• made of an alpha and a beta subunit – 17 types of α chains, 8 types of
β chains
• these ab complexes act as receptors to specific matrix components
• e.g. α1β1 – collagen and laminin
• α5 β1 - fibronectin
Regulation of Programmed Cell Death or APOPTOSIS

• This process is responsible for balancing cell proliferation and maintaining constant cell numbers in
tissues undergoing cell turnover.

• It is also a defense mechanism against virus-infected cells and damaged cells.

• During development, cells no longer necessary (larval tissue) or unwanted (tissue between the digits)
are eliminated by apoptosis.

• Regulation of apoptosis is mediated by the integrated activity of a variety of signaling pathways,

some acting to induce cell death and others to promote cell survival.
•During apoptosis cells die in a regulated, well
programmed fashion, following a sequence of
morphological changes:
• During apoptosis, chromosomal DNA is fragmented as a
result of cleavage between nucleosomes.
• The chromatin condenses and the nucleus breaks up in
small pieces.
• The cell shrinks and breaks up in small membrane-enclosed
fragments called apoptotic bodies.
• These fragments are engulfed and digested by
macrophages.
Proteins involved in apoptosis.

• CASPASES. They all have Cysteine residues at their active site, and cleave after Aspartic Acid
residues in the substrate protein. They are the ultimate effectors of apoptosis, cleaving more
than 40 different target proteins.

• Caspase activity is regulated by the Bcl-2 family. Some members of this family promote
apoptosis, while others inhibit it.

• Promotion of apoptosis involves mitochondrial damage, cytochrome c release, and caspase

activation.
 Refrences

• http://www.sigmaaldrich.com/life-science/cell-biology/cell-biology-products.html?TablePage
=9564359
• http://en.wikipedia.org/wiki/Cytokine
• http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.html
• http://stke.sciencemag.org/content/vol0/issue2003/images/data/CMP_5533/DC3/Moon1-J
W.swf
• http://www.ncbi.nlm.nih.gov/pubmed/16194881
• http://mcb.berkeley.edu/courses/mcb110spring/nogales/mcb110_s2008_4signaling.pdf