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Summary Cell Biology and Immunology
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Cell biology and ImmunologyLECTURE 1 CHAPTER 15 ~ VAN HAASTERT
Principles of cell signaling:
Quorum sensing: many bacteria respond to chemical signals that are secreted by their
neighbors and accumulate at higher population density, this is for coordinate spore
formation, motility, behavior, antibiotic production and sexual conjugation.
Communication between cells in multicellular organisms is mediated mainly by extracellular
signal molecules.
The targets that at the end of signaling pathways are generally called effector proteins.
In the figure you see an intercellular signaling pathway that is activated by an extracellular
signal that binds to a receptor protein in the plasma membrane. Figure 15-1.
Extracellular signals can act over short or long distances:
Place of action:
receptors on cell surface
intracellular receptors
Signal molecules act:
contact-dependent (important during development and in immune responses long distance).
paracrine
synaptic
endocrine (secretes signal molecules, called hormones, into the bloodstream long distance).
paracrine signaling: signaling cells secrete signal molecules into the extracellular fluid, the secreted
molecules are local mediators which act only on cells in the local environment of the signaling cell.
Usually the signaling and target cells are of different cell types, but cells may also produce signals
that they themselves respond to: autocrine signaling.
Synaptic: for long-range signaling mechanisms, the most sophisticated of these are nerve cells, or
neurons. With axons that contact with specialized sites of signal transmission known as chemical
synapses. When the action potential reaches the synapse at the end of the axon, it triggers secretion
of a chemical signal that acts as a neurotransmitter. Figure 15-2 page 815.
Most receptors are transmembrane proteins on the target-cell surface. When these proteins bind
an extracellular signal molecule (a ligand), they become activated and generate intracellular signals
that alter the behavior of the cell.
In other cases, the receptor protein are inside the target cell, and the signal molecule has to enter
the cell to bind to them: this requires that the signal molecule be sufficiently small and hydrophobic
to diffuse across the target cell’s plasma membrane. Figure 15-3 page 816.
1. hydrophilic signal cell surface receptor (mostly)
2. hydrophobic signal intracellular receptor (very often inside the nucleus)
3. gas (gas molecules dissolve in water)
Hydrophobic signal
Figure 15-64 many of it are steroid hormones. Thyroid hormone (schildklier) activates metabolism.
It has four iodine atoms, when you have a lack of iodine and low levels of thyroid hormone, you have
a large thyroid tissue, called Struma (krop). This disease disappeared, when I is used in their bread.
1
,Each cell is programmed to respond to specific combinations of extracellular signals
Many (multicellular)cells require a specific combination of extracellular survival factors to
allow the cell to continue living when deprived of these signals, the cell activates a suicide
program and kills itself, usually by apoptosis a form of programmed cell death.
Cell proliferation often depends on a combination of signals that promote both cell division
and survival, as well as signals that stimulate cell growth. Figure 15-4 page 817.
On the other hand differentiation into a nondividing state called terminal differentiation
frequently requires a different combination of survival and differentiation signals that must
override any signal to divide.
A signal molecule often has different effects on different types of target cells. The neurotransmitter
acetylcholine, for example, decreases the rate of action potential firing in heart pacemaker cells and
stimulates the production of saliva by salivary gland cells, even though the receptors are the same.
The different effects of acetylcholine in these cell types result from differences in the intracellular
signaling proteins, effector proteins, and genes that are activated. Figure 15-5.
There are three major classes of cell-surface receptor proteins
Transduction of hydrophilic signals:
1. ion channel-coupled receptors (transmitter-gated ion channels/ionotropic receptors). Figure 15.6 A
2. G-protein coupled receptors, second messengers figure 15.6 B
3. protein-protein interactions figure 15.6 C
These cell-surface receptors act as signal transducer by converting an extracellular ligand-binding
event into intracellular signals that alter the behavior of the target cell.
Ion channel: a small number of neurotransmitters that open or close an ion channel formed
by the protein to which they bind.
G-protein coupled receptors: a trimeric GTP-binding protein (G-protein) mediates the
interaction between the activated receptor and this target protein.
Protein-protein interaction: enzyme-coupled receptors either function as enzyme or
associate directly with enzymes that they activate. The receptor is heterogeneous in
structure compared with the other two classes.
Cell-surface receptors relay signals via intracellular signaling molecules
Some intracellular signaling molecules are small chemicals, second messengers. Most intracellular
signaling molecules are proteins and behave like molecular switches. When they receive a signal,
they switch from an inactive to an active state, until other process switches them off. The largest
class of molecular switches consist of proteins that are activated or inactivated by phosphorylation.
For these proteins, the switch is thrown in one direction by a protein kinase (adds phosphate
to amino acid) and in the other direction by a proteins phosphatase (removes phosphate).
Figure 15.7A (a molecular switch with G12V mutation in cancer, GTP hydrolysis is G12V).
Protein kinase attach phosphate to the hydroxyl group of specific amino acids on the target proteins.
There are two main types of protein kinase:
1. Serine/threonine kinases, which phosphorylate the hydroxyl groups of serines/threonines.
2. Tyrosine kinases, which phosphorylate proteins on tyrosines.
The other important class of molecular switches consists of GTP-binding proteins.
These proteins switch between an ‘on’ state when GTP is bound and an ‘off’ state when GDP
is bound. On, they usually have GTPase activity and go off by hydrolyzing their GTP to GDP.
There are two major types of GTP-binding proteins:
1. Large, trimeric GTP-binding proteins, help relay signals from G-protein couples receptors
that activate them.
2
, 2. Small, monomeric GTPases, help relay signals from many classes of cell-surface receptors.
GTPase-activating factors (GAPs) drive the proteins into an off state by increasing the rate of
hydrolysis of bound GTP.
Guanine nucleotide exchange factors (GEFs) activate GTP-binding protein by promoting the release
of bound GDP, which allows a new GTP to bind. Figure 15-7/15-8.
It is important, that most signaling pathways have inhibitory steps and a sequence of two inhibitory
steps can have the same effect as one activating step. Figure 15-9 the double-negative activation.
How does a signal remain strong, precise, and specific under the noisy conditions?
High affinity of the interactions between signaling molecules and their correct partner.
The binding of a signaling molecule to the correct target is determined by precise and
complex interactions between complementary surfaces on the two molecules.
The ability of many downstream target proteins to simply ignore such signals. These proteins
respond only when the upstream signal reaches a high concentration or activity level.
Scaffold proteins: bring together groups of interacting signaling proteins into signaling complexes,
often before a signal has been received. Figure 15-10!. Because the scaffold holds the proteins in
close proximity, they can interact at high local concentrations.
The speed of a response depends on the turnover of signaling molecules
When the response requires only changes in proteins already present in the cell, it can occur
very rapidly, like neurotransmitter-gated ion channels that alter the plasma membrane
electrical potential.
When the response involves changes in gene expression and the synthesis of new proteins
requires many minutes or hours. Figure 15-3.
Figure 15-13, with text.
G-protein coupled receptors (GPCRs)
signal molecules:
hormones (adrenaline, dopamine, etc)
taste and odors
light
G-protein coupled receptors form the largest family of cell-surface receptors. Our senses of sight,
smell and taste depend on them. The same signal molecule can activate many different GPCR family
members. GPCRs have a similar structure, figure 15-21.
Trimeric G proteins relay signals from GPCRs
When a signal molecule binds to a GPCR, the receptor undergoes a change that enables it to activate
a trimeric GTP-binding protein, which couples the receptor to enzymes or ion channels in the
membrane.
G proteins are composed of three protein subunits – α, β, γ. In the unstimulated state, the α
has GDP bound and the G protein is inactive. Figure 15-22.
When a GPCR is activated, it acts like a GEF and induces the α to release its bound GDP,
allowing GTP to bind in its place.
GTP binding causes activation, releasing the G protein from the receptor and triggering
dissociation of the GTP-bound Gα subunit form the Gβγ pair. Both interact with various
targets, such as enzymes and ion channels in the plasma membrane. Figure 15-23.
The time required for GTP hydrolysis is usually short because the GTPase activity is greatly
enhanced by the binding of the α subunit to a second protein, which can be either the target
protein or a specific regulator of G protein signaling (RGS).
3
, Some G proteins regulate the production of cyclic AMP
Cyclic AMP (cAMP) acts as a second messenger in some signaling pathways. Figure 15-24, such a
rapid response requires valancing a rapid synthesis of the molecule with its rapid breakdown or
removal.
cAMP is synthesized from ATP by an enzyme called adenylyl cyclase. And it is rapidly
destroyed by cyclic AMP phosphodiesterase’s figure 15-25.
cAMP-dependent protein kinase, phosphorylates mainly metabolic enzymes
in most animal cells, cAMP exerts its effects mainly by activating cyclic-AMP-dependent protein
kinase (PKA). This kinase phosphorylates specific serines or threonines on selected target proteins
including intracellular signaling proteins and effector proteins, thereby regulating their activity. Table
15-1.
In the inactive state, PKA consists of a complex of two catalytic subunits and two regulatory subunits. The binding of cAMP
to the regulatory subunits alters their conformation, causing them to dissociate from the complex. The released catalytic
subunits are there by activated to phosphorylate specific target proteins. Figure 15-26.
The regulatory subunits of PKA (A-kinase) are important for localizing the kinase inside the
cell: special A-kinase anchoring proteins (AKAPs) bind both to the regulatory subunits and to
a component of the cytoskeleton or a membrane of an organelle, thereby tethering the
enzyme complex to a particular subcellular compartment.
Figure 15-27 in cells that secrete the peptide hormone somatostatin, cAMP activates the
gene that encodes this hormone. The regulatory region contains a short cis-regulatory
sequence, called the cyclic AMP response element (CRE). A specific transcription regulator
called CRE-binding (CREB) protein recognizes this sequence.
1. PKA is activated by cAMP
2. Phosphorylates CREB on a single serine
3. Phosphorylated CREB then recruits a transcriptional coactivator called CREB-binding
protein (CBP) which stimulates the transcription of the target genes.
Nitric oxide is a gaseous signaling mediator that passes between cells
Signaling molecules like cyclic nucleotides and calcium are hydrophilic small molecules that generally
act within the cell where they are produced. Gas nitric oxide (NO), acts as a signal molecule in many
tissues of both animals and plants. This is a very hydrophobic and small to pass readily across the
membrane and carry signals to nearby cells.
Acetylcholine stimulates NO synthesis by activating a GPCR on the membrane of the endothelial cells
that line the interior of the vessel. The activated receptor triggers IP 3 synthesis and Ca2+ release,
leading to stimulation of an enzyme that synthesis NO. Figure 15-29. Dissolved NO passes through
the membrane, it diffuse out the cells and goes into neighboring smooth muscle cells, where it
causes muscle relaxation and blood vessel dilation. Figure 15-40.
NO is made by the deamination of the amino acid arginine, catalyzed by enzymes called NO
synthases (NOS).
Protein-protein interaction; signaling through enzyme-coupled receptors
Like GPCRs, enzyme-coupled receptors are transmembrane proteins with their ligand-binding
domain on the outer surface of the plasma membrane.
Activated receptor Tyrosine Kinases (RTKs) phosphorylate themselves
Many extracellular signal proteins act through receptor tyrosine kinases (RTKs). Table 15-4.
There are 60 human RTKs, which classified about 20 structural subfamilies. Figure 15-43.
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