Biology Reference
In-Depth Information
1.3. ROCK and Rho
Rho family proteins (RhoA, RhoB, and RhoC) are part of the larger Ras
superfamily of guanosine triphosphatase hydrolase enzymes (GTPases). Rho
GTPases are key intracellular enzymes, regulating cytoskeleton mechanics
and cellular motility (
Hall, 1998
). These small GTPases exist in inactive
(GDP) and active (GTP) forms, and the cycling between active GTP-bound
and inactive GDP-bound states regulates the growth cone cytoskeleton and
axon growth. Activation of GTPases is catalyzed by guanine-nucleotide
exchange factors (GEFs) that stimulate the release of GDP allowing binding
of GTP. Complementary GTPase-activating proteins stimulate the GTPase
activity of the protein resulting in inactivation. Rho-GDP dissociation
inhibitors (Rho-GDIs) prevent the exchange of GTP for GDP on Rho
GTPases consequently maintaining them in their inactive state. In neurons,
the Rho GTPases are activated by different receptor classes that include the
NgR1 and PirB receptors for myelin-derived growth inhibitory proteins,
the PTP
receptor for CSPGs, and many of the receptors for guidance-type
growth inhibitory proteins that include semaphorins (
Liu & Strittmatter,
2001
), ephrins (
Wahl, Barth, Coiossek, Akoriess, & Mueller, 2000
), and
netrins (
Ailish, Arifa, Sarah, Uwe, & Sarah, 2010
). Receptors for cytokine
signaling, such as TNF, also activate Rho (
Neumann et al., 2002
). The effect
of cytokines on Rho activation is especially relevant to the secondary
response to injury where inflammatory mediators cause the lesion to enlarge
and there is ongoing cell death. Therefore, targeting Rho may also dampen
the acute secondary response to injury as part of its neuroprotective activity
(see below) (
Fig. 6.1
).
ROCK is a downstream serine threonine kinase whose activity is
stimulated upon Rho activation. There are two ROCK isoforms, ROCKI
and ROCKII, with ROCK II being more highly expressed in the CNS than
ROCKI. ROCK I has a more general distribution than ROCKII (
Duffy
et al., 2009; Mueller, Mack, & Teusch, 2005
). Rho activation and the
downstream activation of Rho-associated kinase signal through a variety of
proteins to rearrange the actin and microtubule cytoskeleton, ultimately
resulting in a collapse of the growth cone scaffold and axon growth arrest.
One of the newly identified targets of ROCK is the phosphatase and
tensin homologue (PTEN) (
Li et al., 2005
) which is a phosphatase that acts
as a tumor suppressor. PTEN is directly activated by ROCK, and in the
CNS, blocking PTEN activity strongly promotes axon regeneration, in part
through mTOR-dependent upregulation of growth-associated proteins
s
