Biomedical Engineering Reference
In-Depth Information
dependently, they are, in fact, highly interrelated [105]. An increasing amount
of data suggests that these processes are coupled through complicated feed-
back mechanisms, which in many cases are at least partially mechanical
[4, 77, 106]. For example, it has been shown that intrinsic or extrinsic forces
affect focal adhesion strength and turnover [4, 77]. Furthermore, there is ev-
idence for feedback between actin polymerization, myosin activity, and ad-
hesion, where a perturbation in one of these leads to the reorganization and
modulation of the behavior of the others [106]. As mentioned earlier, mea-
surements of the protrusive forces in growing dendritic actin networks [71, 72]
also suggest that actin network growth and organization are dependent on
mechanical parameters. These results indicate that the organization and me-
chanical characteristics of the individual elements involved in cell motility are
not fixed, but rather depend on the dynamics of the entire system. These com-
plex interrelationships between different modules are characteristic of biologi-
cal systems, and emphasize the need for an integrative system-level approach
for understanding cell motility.
The integration of numerous molecular components and multiple modules
to achieve coherent cell movement requires a high degree of coordination.
Multiple signaling pathways have been shown to play important roles in such
coordination, and in establishing and maintaining cell polarity (reviewed in
[8]). The Rho signaling pathway is one of the important regulators of pro-
trusion; members of the Rho family such as Rac and Cdc42 are thought to
stimulate Arp2/3 activation and protrusion at the leading edge via the WASP
proteins, while other members such as Rho are important for defining the rear
of the cell. The phosphoinositides, PtdIns(3,4,5)P
3
(PIP
3
) and PtdIns(3,4)P
2
(PIP
2
), have been shown to be important for the polarized response of cells to
chemoattractant gradients [107]. For example, upon receptor activation dur-
ing chemotaxis, phospho-inositide 3-kinases (PI3Ks) which catalyze the phos-
phorylation of PIP
2
to PIP
3
, are recruited to the membrane and generate
an accumulation of PIP
3
at the leading edge of cells. While these signaling
pathways have been shown to be essential in other cell types such as neu-
trophils and
Dictyostelium
, their role in keratocytes, which are not responsive
to external chemical cues, is not clear. For example, Rho-kinase dependent
myosin activity is required for establishing polarity and motility initiation in
keratocytes [31], but its inhibition had essentially no effect on steady state
motility, indicating that this pathway is not essential for maintaining polarity
in keratocytes. Similarly, PIP
3
does not localize to the leading edge of mov-
ing keratocytes, and inhibition of PI3Ks does not have a significant effect on
cell speed (P.T. Yam and N.A. Dye, unpublished observations). As illustrated
by several examples throughout this chapter (e.g., the mechanosensitivity of
adhesions and the load dependence of protrusion) mechanical processes also
play an important role in large-scale coordination. Further work is required to
determine the relative role of mechanical coupling and the inherent dynamics
of the system and signaling processes in large-scale coordination in keratocyte
motility.
