Transcript Cell Signalling

Cell Signalling
M. Metodiev
2011/2012
To make multicellular organisms cell must communicate. This
communication is mediated by extracellular signal molecules.
Sofisticated mechanisms control which signal molecules are
released from a specific type of cell, at what time and concentration
they are secreted, and how these signals are interpreted by the
target cells
Some signalling molecules act over long distances, some act only on
the immediate neighbour cells
Most cells in higher organisms are both emiters and receivers of
signals
Lecture 1: General Principles of Cell Signalling
• Signals, receptors and mediators
• The prototypical pheromone signalling pathway of
budding yeast
• Cell surface and intracellular receptors
• Types of intercellular signalling
• Nuclear receptor signalling
• Types of cell surface receptors
• Molecular switches: signalling through GTPases and
protein phosphorylation
Lecture 2: Discovery and elucidation of novel signalling
pathways: a case study
Budding yeast cells responding to mating factor.
(A) The cells are normally spherical.
(B) In response to mating factor secreted by neighbouring
yeast cells, they put out a protrusion toward the
source of the factor in preparation for mating.
The binding of extracellular signal
molecules to either cell-surface receptors or
intracellular receptors.
Most signal molecules are hydrophilic and
are therefore unable to cross the plasma
membrane directly; instead, they bind to
cell-surface receptors, which in turn
generate one or more signals inside the
target cell.
Some small signal molecules, by contrast,
diffuse across the plasma membrane and
bind to receptors inside the target cell
either in the cytosol or in the nucleus (as
shown here). Many of these small signal
molecules are hydrophobic and nearly
insoluble in aqueous solutions; they are
therefore transported in the bloodstream
and other extracellular fluids after binding
to carrier proteins, from which they
dissociate before entering the target cell.
Forms of intercellular signaling.
(A) Contact-dependent signaling requires cells to be in direct membrane-membrane
contact.
(B) Paracrine signaling depends on signals that are released into the extracellular space
and act locally on neighboring cells.
(C) Synaptic signaling is performed by neurons that transmit signals electrically along
their axons and release neurotransmitters at synapses, which are often located far away
from the cell body.
(D) Endocrine signaling depends on endocrine cells, which secrete hormones into the
bloodstream that are then distributed widely throughout the body. Many of the same
types of signaling molecules are used in paracrine, synaptic, and endocrine signaling;
the crucial differences lie in the speed and selectivity with which the signals are
delivered to their targets.
The contrast between endocrine and synaptic
signaling. In complex animals, endocrine cells and
nerve cells work together to coordinate the diverse
activities of the billions of cells. Whereas different
endocrine cells must use different hormones to
communicate specifically with their target cells,
different nerve cells can use the same neurotransmitter
and still communicate in a highly specific manner.
(A) Endocrine cells secrete hormones into the blood,
which signal only the specific target cells that
recognize them. These target cells have receptors for
binding a specific hormone, which the cells “pull”
from the extracellular fluid.
(B) In synaptic signaling, by contrast, specificity arises
from the synaptic contacts between a nerve cell and
the specific target cells it signals. Usually, only a target
cell that is in synaptic communication with a nerve cell
is exposed to the neurotransmitter released from the
nerve terminal (although some neurotransmitters act
in a paracrine mode, serving as local mediators that
influence multiple target cells in the area).
An animal cell's dependence on multiple extracellular signals. Each cell type displays a
set of receptors that enables it to respond to a corresponding set of signal molecules
produced by other cells. These signal molecules work in combinations to regulate the
behaviour of the cell. As shown here, an individual cell requires multiple signals to
survive (blue arrows) and additional signals to divide (red arrow) or differentiate (green
arrows). If deprived of appropriate survival signals, a cell will undergo a form of cell
suicide known as programmed cell death, or apoptosis.
The nuclear receptor superfamily. All nuclear
hormone receptors bind to DNA as either
homodimers or heterodimers, but for
simplicity we show them as monomers here.
(A) The receptors all have a related structure.
The short DNA-binding domain in each
receptor is shown in green. (B) A receptor
protein in its inactive state is bound to
inhibitory proteins. Domain-swap
experiments suggest that many of the ligandbinding, transcription-activating, and DNAbinding domains in these receptors can
function as interchangeable modules. (C) The
binding of ligand to the receptor causes the
ligand-binding domain of the receptor to
clamp shut around the ligand, the inhibitory
proteins to dissociate, and coactivator
proteins to bind to the receptor's
transcription-activating domain, thereby
increasing gene transcription. (D) The threedimensional structure of a ligand-binding
domain with (right) and without (left) ligand
bound. Note that the blue α helix acts as a lid
that snaps shut when the ligand (shown in
red) binds, trapping the ligand in place.
Responses induced by the activation of a nuclear hormone receptor. (A) Early primary
response and (B) delayed secondary response. The figure shows the responses to a steroid
hormone, but the same principles apply for all ligands that activate this family of receptor
proteins. Some of the primary-response proteins turn on secondary-response genes, whereas
others turn off the primary-response genes. The actual number of primary- and secondaryresponse genes is greater than shown. As expected, drugs that inhibit protein synthesis
suppress the transcription of secondary-response genes but not primary-response genes,
allowing these two classes of gene transcription responses to be readily distinguished.
Three classes of cell-surface
receptors.
(A) Ion-channel-linked
receptors
(B) G-protein-linked receptors
(C) enzyme-linked receptors
Although many enzyme-linked
receptors have intrinsic
enzyme activity, as shown on
the left, many others rely on
associated enzymes
Different kinds of intracellular signaling
proteins along a signaling pathway from
a cell-surface receptor to the nucleus.
In this example, a series of signaling
proteins and small intracellular
mediators relay the extracellular signal
into the cell, causing a change in gene
expression.
The signal is amplified, altered
(transduced), and distributed en route.
Many of the steps can be modulated by
other extracellular and intracellular
signals, so that the final result of one
signal depends on other factors
affecting the cell.
Ultimately, the signaling pathway
activates (or inactivates) target proteins
that alter cell behavior. In this example,
the target is a gene regulatory protein.
Two types of intracellular signaling proteins that act as molecular switches. In both cases, a
signaling protein is activated by the addition of a phosphate group and inactivated by the
removal of the phosphate. (A) The phosphate is added covalently to the signaling protein
by a protein kinase. (B) A signaling protein is induced to exchange its bound GDP for GTP.
To emphasize the similarity in the two mechanisms, ATP is shown as APPP, ADP as APP, GTP
as GPPP, and GDP as GPP.
Signal integration
Extracellular signals A and B both
activate a different series of protein
phosphorylations, each of which
leads to the phosphorylation of
protein Y but at different sites on the
protein. Protein Y is activated only
when both of these sites are
phosphorylated, and therefore it
becomes active only when signals A
and B are simultaneously present. For
this reason, integrator proteins are
sometimes called coincidence
detectors.
Intracellular signalling complexes enhance the speed, the efficiency,
and the specificity of the response
A specific signalling complex can be formed using modular interaction
domains
Signalling through G-protein-coupled cell-surface receptors
Cyclic AMP is synthesized by
the adenylyl cyclase from
ATP. It is a cyclization
reaction that removes two
phosphates as
pyrophosphate.
Cyclic AMP is short-lived. It is
rapidly hydrolyzed by
phosphodiesterases to give
5’-AMP as shown on the
figure.
The pyrophosphate is
hydrolyzed to inorganic
phosphates. This reaction is
the thermodynamic driver
for the synthesis of cAMP.
A cultured nerve cell responding to the neurotransmiter serotonin. Serotonin acts
through a GPCR and activates cAMP synthesis. The cells express a fluorescent proteins
that changes its fluorescence upon binding of cAMP. Blue indicate low concentration of
cAMP, yellow – intermediate and, red a high concentration of cAMP.