Essential Cell Biology 5th edition

Enzyme-Coupled Receptors
559
interaction domains allow intracellular signaling proteins to recognize
phosphorylated lipids that are produced on the cytosolic side of the
plasma membrane in response to certain signals, as we discuss later.
As long as they remain together, the signaling protein complexes assembled
on the cytosolic tails of the RTKs can transmit a signal along several
routes simultaneously to many destinations in the cell, thus activating
and coordinating the numerous biochemical changes that are required to
trigger a complex response such as cell proliferation or differentiation. To
help terminate the response, the tyrosine phosphorylations are reversed
by tyrosine phosphatases, which remove the phosphates that were added
to the tyrosines of both the RTKs and other intracellular signaling proteins
in response to the extracellular signal. In some cases, activated
RTKs (as well as some GPCRs) are inactivated in a more brutal way: they
are dragged into the interior of the cell by endocytosis and then destroyed
by digestion in lysosomes (as discussed in Chapter 15).
Different RTKs recruit different collections of intracellular signaling proteins,
producing different effects; however, certain components are used
by most RTKs. These include, for example, a phospholipase C that functions
in the same way as the phospholipase C activated by GPCRs to
trigger the inositol phospholipid signaling pathway discussed earlier (see
Figure 16–23). Another intracellular signaling protein that is activated by
almost all RTKs is a small GTP-binding protein called Ras, as we discuss
next.
Most RTKs Activate the Monomeric GTPase Ras
As we have seen, activated RTKs recruit and activate many kinds of
intracellular signaling proteins, leading to the formation of large signaling
complexes on the cytosolic tail of the RTK. One of the key members
of these signaling complexes is Ras—a small GTP-binding protein that
is bound by a lipid tail to the cytosolic face of the plasma membrane.
Virtually all RTKs activate Ras, including platelet-derived growth factor
(PDGF) receptors, which mediate cell proliferation in wound healing, and
nerve growth factor (NGF) receptors, which play an important part in the
development of certain vertebrate neurons.
The Ras protein is a member of a large family of small GTP-binding proteins,
often called monomeric GTPases to distinguish them from the
trimeric G proteins that we encountered earlier. Ras resembles the α subunit
of a G protein and functions as a molecular switch in much the same
way. It cycles between two distinct conformational states—active when
GTP is bound and inactive when GDP is bound. Interaction with an activating
protein called Ras-GEF encourages Ras to exchange its GDP for
GTP, thus switching Ras to its activated state (Figure 16–30); after a delay,
Ras is switched off by a GAP called Ras-GAP (see Figure 16–12), which
promotes the hydrolysis of its bound GTP to GDP (Movie 16.7).
EXTRACELLULAR
SPACE
CYTOSOL
activated RTK
P
P
P
adaptor protein
signal molecule
P
P
P
inactive Ras protein
GDP
Ras-GEF
GDP
GTP
plasma membrane
activated Ras protein
GTP
ONWARD
TRANSMISSION
OF SIGNAL
Figure 16–30 RTKs activate Ras. An adaptor
protein docks on a particular phosphotyrosine
on the activated receptor (the other signaling
proteins that would be bound to the receptor,
as shown in Figure 16–29, have been
omitted for simplicity). The adaptor recruits
a Ras guanine nucleotide exchange factor
(Ras‐GEF) that stimulates Ras to exchange
its bound GDP for GTP. The activated
Ras protein can now stimulate several
downstream signaling pathways, one of which
is shown in Figure 16–31. Note that the Ras
protein contains a covalently attached lipid
group (red ) that helps anchor the protein to
the inside of the plasma membrane.