Essential Cell Biology 5th edition

542 CHAPTER 16 Cell Signaling
Figure 16–11 Many intracellular signaling
proteins act as molecular switches. These
proteins can be activated—or in some cases
inhibited—by the addition or removal of a
phosphate group. (A) In one class of switch
protein, the phosphate is added covalently
by a protein kinase, which transfers the
terminal phosphate group from ATP to
the signaling protein; the phosphate is
then removed by a protein phosphatase.
(B) In the other class of switch protein, a
GTP-binding protein is activated when it
exchanges its bound GDP for GTP (which, in
a sense, adds a phosphate to the protein);
the protein then switches itself off by
hydrolyzing its bound GTP to GDP.
(A)
SIGNAL
IN
ATP
ADP
protein
kinase
OFF
ON
protein
phosphatase
SIGNAL
OUT
SIGNALING BY
PROTEIN PHOSPHORYLATION
P
P
SIGNAL
IN
GDP
GTP
(B)
GTP
binding
OFF
GDP
ON
GTP
GTP
hydrolysis
SIGNAL
OUT
SIGNALING BY GTP-BINDING PROTEINS
P
unstimulated state. Thus, for every activation step along the pathway,
there exists an inactivation mechanism. The two are equally important
for a signaling pathway to be useful.
GDP
GTP
INACTIVE
MONOMERIC GTPase
GEF
OFF
GDP
ON
GTP
GAP
ACTIVE
MONOMERIC GTPase
Figure 16–12 The activity of monomeric
GTPases is controlled by two types of
regulatory proteins. Guanine nucleotide
exchange factors (GEFs) promote the
exchange ECB5 of GDP e16.16/16.12 for GTP, thereby switching
the protein on. GTPase-activating proteins
(GAPs) stimulate the hydrolysis of GTP to
GDP, thereby switching the protein off.
P
Proteins that act as molecular switches fall mostly into one of two
classes. The first—and by far ECB5 the e16.15/16.11
largest—class consists of proteins that
are activated or inactivated by phosphorylation, a chemical modification
discussed in Chapter 4 (see Figure 4−46). For these molecules, the switch
is thrown in one direction by a protein kinase, which covalently attaches
a phosphate group onto the switch protein, and in the opposite direction
by a protein phosphatase, which takes the phosphate off again (Figure
16–11A). The activity of any protein that is regulated by phosphorylation
depends—moment by moment—on the balance between the activities of
the protein kinases that phosphorylate it and the protein phosphatases
that dephosphorylate it.
Many of the switch proteins controlled by phosphorylation are themselves
protein kinases, and these are often organized into phosphorylation cascades:
one protein kinase, activated by phosphorylation, phosphorylates
the next protein kinase in the sequence, and so on, transmitting the signal
onward and, in the process, amplifying, distributing, and regulating
it. Two main types of protein kinases operate in intracellular signaling
pathways: the most common are serine/threonine kinases, which—as
the name implies—phosphorylate proteins on serines or threonines; others
are tyrosine kinases, which phosphorylate proteins on tyrosines.
The other class of switch proteins involved in intracellular signaling pathways
are GTP-binding proteins. These toggle between an active and
an inactive state depending on whether they have GTP or GDP bound
to them, respectively (Figure 16–11B). Once activated by GTP binding,
many of these proteins have intrinsic GTP-hydrolyzing (GTPase) activity,
and they shut themselves off by hydrolyzing their bound GTP to GDP.
Two main types of GTP-binding proteins participate in intracellular signaling.
The first type—the large, trimeric GTP-binding proteins (also called
G proteins)—relay messages from G-protein-coupled receptors. We discuss
this major class of GTP-binding proteins in detail shortly.
Other cell-surface receptors rely on a second type of GTP-binding protein—the
small, monomeric GTPases—to help relay their signals. These
switch proteins are generally aided by two sets of regulatory proteins that
help them bind and hydrolyze GTP: guanine nucleotide exchange factors
(GEFs) activate the switches by promoting the exchange of GDP for GTP,
and GTPase-activating proteins (GAPs) turn them off by promoting GTP
hydrolysis (Figure 16–12).