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

1078 Chapter 19: Cell Junctions and the Extracellular Matrix
thrombin
inactive
integrin
active
integrin
Rap1
thrombin
receptor
GDP
GDP
GTP
GTP
GTP
RIAM
RIAM
vinculin
CYTOSOL
RIAM
kindlin
active talin
inactive talin
actin filament
Figure 19–58 Activation of integrins by intracellular signaling. Signals received from outside the cell can act through various
intracellular mechanisms to stimulate integrin activation. In platelets, as illustrated here, the extracellular signal protein thrombin
activates a G-protein-coupled receptor on the cell surface, thereby initiating a signaling pathway that leads to activation of
Rap1, a member of the monomeric GTPase family. Activated Rap1 interacts with the protein RIAM, which then recruits talin to
the plasma membrane. Together with another protein called kindlin, talin interacts with the integrin β chain to trigger integrin
activation. Talin then interacts with adaptor proteins such as vinculin, resulting in the formation of an actin linkage (see Figure
19–55).
Talin regulation depends in part on an interaction between its flexible C-terminal rod domain and the N-terminal head domain
that contains the integrin-binding site. This interaction is thought to maintain talin in an inactive state when it is free in the
cytoplasm. When talin is recruited by RIAM to the plasma membrane, the talin head domain interacts with a phosphoinositide
called PI(4,5)P 2 (not shown here, but see Figure 15–28), resulting in dissociation of the rod domain. Talin unfolds to expose its
binding sites for integrin and other MBoC6 proteins. m19.49/19.59
hooked together, preventing their interaction with cytoskeletal linker proteins.
In the active state, the two integrin subunits are unhooked at the membrane to
expose the intracellular binding sites for cytoplasmic adaptor proteins, and the
external domains unfold and extend, like a pair of legs, to expose a high-affinity
matrix-binding site at the tips of the subunits. Thus, the switch from inactive
to active states depends on a major conformational change that simultaneously
exposes the external and internal ligand-binding sites at the ends of the integrin
molecule. External matrix binding and internal cytoskeleton linkages are thereby
coupled.
Switching between the inactive and active states is regulated by a variety of
mechanisms that vary, depending on the needs of the cell. In some cases, activation
occurs by an “outside-in” mechanism: the binding of an external matrix protein,
such as the RGD sequence of fibronectin, can drive some integrins to switch
from the low-affinity inactive state to the high-affinity active state. As a result,
binding sites for talin and other cytoplasmic adaptor proteins are exposed on the
tail of the β chain. The binding of these adaptor proteins then leads to attachment
of actin filaments to the intracellular end of the integrin molecule (see Figure
19–55). In this way, when the integrin catches hold of its ligand outside the cell,
the cell reacts by tying the integrin molecule to the cytoskeleton, so that force can
be applied at the point of cell attachment.
The chain of cause and effect can also operate in reverse, from inside to outside.
This “inside-out” integrin-activation process generally depends on intracellular
regulatory signals that stimulate the ability of talin and other proteins to
interact with the β chain of the integrin. Talin competes with the integrin α chain
for its binding site on the tail of the β chain. Thus, when talin binds to the β chain,
it blocks the intracellular α–β linkage, allowing the two legs of the integrin molecule
to spring apart.
The regulation of “inside-out” integrin activation is particularly well understood
in platelets, where an extracellular signal protein called thrombin binds
to a specific G-protein-coupled receptor (GPCR) on the cell surface and thereby
activates an intracellular signaling pathway that leads to integrin activation (Figure
19–58). It is likely that similar signaling pathways govern integrin activation in
numerous other cell types.