Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

824 Chapter 15: Cell Signaling
activated
receptor
P
extracellular
signal molecule
P
P
P
P
P
PH
PTB
P
P
SH2
IRS1 (docking protein)
SH3
SH3
phosphoinositide
docking sites
P
P
P
Another way of bringing receptors and intracellular signaling proteins together
is to concentrate them in a specific region of the cell. An important example is the
primary cilium that projects like an antenna from the surface of most vertebrate
MBoC6 m15.22/15.11
cells (discussed in Chapter 16). It is usually short and nonmotile and has microtubules
in its core, and a number of surface receptors and signaling proteins are
concentrated there. We shall see later that light and smell receptors are also highly
concentrated in specialized cilia.
PH
Sos
Grb2 (adaptor protein)
scaffold protein
plasma
membrane
CYTOSOL
Figure 15–11 A specific signaling
complex formed using modular
interaction domains. This example is
based on the insulin receptor, which is
an enzyme-coupled receptor (a receptor
tyrosine kinase, discussed later). First,
the activated receptor phosphorylates
itself on tyrosines, and one of the
phosphotyrosines then recruits a docking
protein called insulin receptor substrate-1
(IRS1) via a PTB domain of IRS1; the PH
domain of IRS1 also binds to specific
phosphoinositides on the inner surface of
the plasma membrane. Then, the activated
receptor phosphorylates IRS1 on tyrosines,
and one of these phosphotyrosines binds
the SH2 domain of the adaptor protein
Grb2. Next, Grb2 uses one of its two SH3
domains to bind to a proline-rich region of
a protein called Sos, which relays the signal
downstream by acting as a GEF (see Figure
15–8) to activate a monomeric GTPase
called Ras (not shown). Sos also binds to
phosphoinositides in the plasma membrane
via its PH domain. Grb2 uses its other SH3
domain to bind to a proline-rich sequence
in a scaffold protein. The scaffold protein
binds several other signaling proteins, and
the other phosphorylated tyrosines on IRS1
recruit additional signaling proteins that
have SH2 domains (not shown).
The Relationship Between Signal and Response Varies in Different
Signaling Pathways
The function of an intracellular signaling system is to detect and measure a specific
stimulus in one location of a cell and then generate an appropriately timed
and measured response at another location. The system accomplishes this task
by sending information in the form of molecular “signals” from the sensor to the
target, often through a series of intermediaries that do not simply pass the signal
along but process it in various ways. All signaling systems do not work in precisely
the same way: each has evolved specialized behaviors that produce a response
that is appropriate for the cell function that system controls. In the following paragraphs,
we list some of these behaviors and describe how they vary in different
systems, as a foundation for more detailed discussions later.
1. Response timing varies dramatically in different signaling systems, according
to the speed required for the response. In some cases, such as synaptic
signaling (see Figure 15–2C), the response can occur within milliseconds.
In other cases, as in the control of cell fate by morphogens during development,
a full response can require hours or days.
2. Sensitivity to extracellular signals can vary greatly. Hormones tend to act
at very low concentrations on their distant target cells, which are therefore
highly sensitive to low concentrations of signal. Neurotransmitters, on the
other hand, operate at much higher concentrations at a synapse, reducing
the need for high sensitivity in postsynaptic receptors. Sensitivity is often
controlled by changes in the number or affinity of the receptors on the target
cell. A particularly important mechanism for increasing the sensitivity
of a signaling system is signal amplification, whereby a small number of
activated cell-surface receptors evoke a large intracellular response either
by producing large amounts of a second messenger or by activating many
copies of a downstream signaling protein.
3. Dynamic range of a signaling system is related to its sensitivity. Some systems,
like those involved in simple developmental decisions, are responsive