Biology Reference
In-Depth Information
achieved in a number of ways, but in nonneuronal cells it is ultimately
dependent on the presence of talin and kindlins, which bind to the C-terminal
of the
b
subunit (
Anthis & Campbell, 2011; Kim, Ye, & Ginsberg, 2011;
Moser, Legate, Zent, & Fassler, 2009
). Talin activation alters the structure
of the
b
1 integrin transmembrane domain, initiating a conformation change
in the extracellular domain, and thereby increasing the ability to bind to
ligands (
Askari, Buckley, Mould, & Humphries, 2009
). This is facilitated
by kindlin proteins, and their joint action forces the integrins into a high-
affinity state. Talin also relies on activation by signaling molecules, so that
inside-out activation of integrins is complex and ultimately governed by nu-
merous signaling molecules including calcium, diacylglycerol, Rap1, pho-
sphatidylinositol (4,5)-bisphosphate, and calpain (
Anthis & Campbell,
2011; Moser et al., 2009
). The extent to which integrins are regulated by
talin and kindlins in axons is not completely understood, but talin is report-
edly present at the tips of growth cone filopodia (
Myers et al., 2011;
Renaudin, Lehmann, Girault, &McKerracher, 1999
) and kindlin-2 expres-
sion is evident in the brain and in cultured central and peripheral neurons,
where it is involved in regulating integrin activation and axon growth (
Tan
et al., 2012
). Once bound to a ligand, integrins change cell behavior by ini-
tiating outside-in signaling and linking to the cytoskeleton within adhesion
complexes. These focal adhesion complexes are referred to as point contacts
when described at the growth cone (
Renaudin et al., 1999
). Focal adhesions
are well characterized and consist of scaffold proteins such as talin, vinculin,
and paxillin that link the complex to the actin cytoskeleton, and numerous
signaling and adapter molecules such as focal adhesion kinase (FAK) and Src
that regulate the complex and propagate outside-in signaling (
Huttenlocher
& Horwitz, 2011; Parsons, 2003
). Growth cone point contacts are less well
described but contain all the key components of focal adhesions listed above
(
Renaudin et al., 1999; Robles & Gomez, 2006
), so it is likely that integrins
function at the growth cone in a similar fashion to other cellular locations,
although they may be subject to regulation that is specific to the growth
cone. Finally, integrin function is further regulated by trafficking, which
has been shown to be an important determinant for adhesion, spreading, mi-
gration, and cancer invasion (
Caswell & Norman, 2008; Jones, Caswell, &
Norman, 2006; Margadant, Monsuur, Norman, & Sonnenberg, 2011;
Pellinen & Ivaska, 2006; Ulrich &Heisenberg, 2009
), processes that are sim-
ilar to growth cone behavior during axon extension. Integrin endocytosis is
required for the disassembly of focal adhesions (
Chao &Kunz, 2009; Ezratty,
Bertaux, Marcantonio, & Gundersen, 2009; Ezratty, Partridge, &
