Biology Reference
In-Depth Information
(
Kim et al., 2006
). Moreover, Cdk5 forms a complex with
a
-chimaerin, a
GAP specific for Rac and Cdc42, implicating the role of Cdk5 in the
regulation of actin polymerization (
Qi, Ching, Kung, & Wang, 2004
).
Interestingly, some of the Cdk5-dependent phosphorylation events appear
to regulate Rho GTPase activity in an indirect manner. For example,
phosphorylation of RasGRF1 by Cdk5 leads to calpain-dependent
degradation of the protein (
Kesavapany et al., 2006
). In addition, Cdk5-
mediated phosphorylation prevents p27
kip1
from proteasome-dependent
protein degradation, allowing the stabilized p27
kip1
to suppress the RhoA
signaling (
Kawauchi et al., 2006
). Nevertheless, the regulation of RhoA
activity by Cdk5 is dependent on specific cellular context. Cdk5-mediated
phosphorylation of ephexin 1 enhances its activity toward RhoA during
the process of dendritic spine retraction (
Fu et al., 2007
). Moreover, Cdk5
inhibits RasGRF2-mediated Rac activity (
Kesavapany et al., 2004
), while
Cdk5 has also been observed to enhance Rac activity through
phosphorylation of kalirin-7 (
Xin et al., 2008
). These observations
collectively demonstrate that Cdk5 regulates Rho GTPase activity, and
that coordinated regulation of Rho GTPase signaling by Cdk5 enables
efficient actin remodeling to support axon growth.
2.3.2 Cdk5 as a modulator of microtubule dynamics
Aside from actin reorganization, microtubule dynamics is of equal impor-
tance for axon formation. Microtubules have been demonstrated to play
an instructive role in navigating growth cone and subsequently regulating
axon growth, since local assembly and stabilization of microtubule on
one side of the growth cone is sufficient to induce directional axon growth
(
Conde & Caceres, 2009
).
Microtubule dynamics is regulated by a wide range of microtubule-
associated proteins (MAPs). The interaction between MAPs and microtu-
bules is tightly controlled by phosphorylation events, implicating the
importance of protein kinases in orchestrating this process. Among these
kinases, Cdk5 and GSK-3
b
regulate microtubule assembly and dynamics
through phosphorylation of various MAPs. However, they exhibit opposite
effects on axon development. While GSK-3
b
functions as a negative regu-
lator of axon formation (
Jiang, Guo, Liang, &Rao, 2005
), Cdk5 contributes
to axonogenesis (
Paglini et al., 1998
). Furthermore, Cdk5 has been
suggested to negatively regulate GSK-3
b
activity, since inhibition of
Cdk5 reduced inhibitory phosphorylation of GSK-3
b
at Ser9, resulting in
activation of in neurons (
Morfini et al., 2004
).
