Essential Cell Biology 5th edition

Enzyme-Coupled Receptors
561
survival signal
plasma membrane
inositol phospholipid
EXTRACELLULAR SPACE
P
P
P P P P
P
P P
P
P P
P
CYTOSOL
activated RTK
activated
PI 3-kinase
phosphorylated
inositol
phospholipid
protein
kinase 1
Akt
P P
protein
kinase 2
SIGNAL RELAYED ONWARD
BY ACTIVATED Akt
Figure 16–32 Some RTKs activate the PI-3-kinase–Akt signaling pathway.
An extracellular survival signal, such as IGF, activates an RTK, which recruits and
activates PI 3-kinase. PI 3-kinase then phosphorylates an inositol phospholipid
that is embedded in the cytosolic side of the plasma membrane. The resulting
phosphorylated inositol phospholipid ECB5 e16.35/16.32
attracts intracellular signaling proteins that
have a special domain that recognizes it. One of these signaling proteins, Akt, is
a protein kinase that is activated at the membrane by phosphorylation mediated
by two other protein kinases (here called protein kinases 1 and 2); protein kinase
1 is also recruited by the phosphorylated lipid docking sites. Once activated, Akt
is released from the plasma membrane and phosphorylates various downstream
proteins on specific serines and threonines (not shown).
growth factor (IGF) family, act through RTKs. One crucially important
signaling pathway that these RTKs activate to promote cell growth and
survival involves the enzyme phosphoinositide 3-kinase (PI 3-kinase),
which phosphorylates inositol phospholipids in the plasma membrane.
These phosphorylated lipids serve as docking sites for specific intracellular
signaling proteins, which relocate from the cytosol to the plasma
membrane, where they can activate one another. One of the most important
of these relocated signaling proteins is the serine/threonine kinase
Akt (Figure 16–32).
Akt, also called protein kinase B (PKB), promotes the growth and survival
of many cell types, often by inactivating the signaling proteins it phosphorylates.
For example, Akt phosphorylates and inactivates a cytosolic
protein called Bad. In its active state, Bad encourages the cell to kill itself
by indirectly activating a cell-suicide program called apoptosis (discussed
in Chapter 18). Phosphorylation by Akt thus promotes cell survival by
inactivating a protein that otherwise promotes cell death (Figure 16–33).
In addition to promoting cell survival, the PI-3-kinase–Akt signaling
pathway stimulates cells to grow in size. It does so by indirectly activating
QUESTION 16–7
Would you expect to activate
RTKs by exposing the exterior of
cells to antibodies that bind to the
respective proteins? Would your
answer be different for GPCRs?
(Hint: review Panel 4–2, on
pp. 140–141, regarding the
properties of antibody molecules.)
Bad
active Akt
survival signal
P P P
PHOSPHORYLATION OF Bad
RELEASES ACTIVE Bcl2
inactive Bcl2
active Bcl2
inactive Bad
PROMOTION OF CELL
SURVIVAL BY INHIBITION
OF APOPTOSIS
Figure 16–33 Activated Akt promotes
cell survival. One way it does so is by
phosphorylating and inactivating a protein
called Bad. In its unphosphorylated
state, Bad promotes apoptosis (a form of
cell death) by binding to and inhibiting
a protein, called Bcl2, which otherwise
suppresses apoptosis. When Bad is
phosphorylated by Akt, Bad releases Bcl2,
which now blocks apoptosis, thereby
promoting cell survival.