Biology Reference
In-Depth Information
Cdk5 itself elicits nokinase activity and requires associationwith its regulatory
subunit proteins, p35 or p39, for activation. In accordance with the essential
roles of p35 or p39 in activating Cdk5, although Cdk5 is ubiquitously
expressed in all tissues, the highest expression and its activity is restricted
largely to the nervous system where p35 and p39 are predominantly
expressed (
Dhavan & Tsai, 2001
).
Initial characterization of Cdk5 function came from transgenic animal
studies. Genetic ablation of
cdk5
gene led to perinatal lethality and abnormal
neural architecture characterizedbydefective cortical laminationand axonpro-
jection (
Fu et al., 2005; Ohshima et al., 1996
). As essential activators of Cdk5,
p35 and p39 are functionally redundant, since p35- or p39-deficient mice only
exhibited a milder phenotype or no phenotype, respectively. Remarkably,
targeted deletion of both p35 and p39 gene displayed an identical phenotype
compared to that of mice lacking Cdk5 (
Ko et al., 2001
), thus underscoring
the indispensible roles of p35 and p39 in activating Cdk5
in vivo
. Aside from
activation by its unique regulatory subunits, Cdk5 activity is also regulated
by posttranslational modifications. The kinase activity of Cdk5 is enhanced
upon phosphorylation at Tyr15 by nonreceptor tyrosine kinases such as Fyn
and Abl, or receptor tyrosine kinases such as EphA4 and TrkB (
Lalioti,
Pulido, & Sandoval, 2010
). On the other hand, Cdk5 activity is negatively
regulated by S-nitrosylation at Cys83 (
Zhang et al., 2010
).
In addition to regulating cortical lamination, Cdk5 has been implicated
in almost all aspects of brain development and function, from neuronal dif-
ferentiation and cell survival, to synaptic plasticity and neurodegenerative
diseases (
Su & Tsai, 2011
). Despite its evident role in axon growth and guid-
ance during development, Cdk5 is increasingly implicated in various cellular
events that affect axon repair, outgrowth, and regeneration after injury.
Indeed, one initial study reported that Cdk5 activation is involved in periph-
eral axon regeneration after facial nerve crush injury (
Namgung et al., 2004
).
Nevertheless, whether Cdk5 regulates axon regeneration in mammalian
CNS in a positive or negative manner is currently unclear. Next, we review
various Cdk5-mediated signaling pathways that regulate axon growth and
regeneration.
2.2. Transducing extracellular signals
Initiation and elongation of axons are guided by extracellular factors such as
neurotrophins or axon guidance cues. Thus, regulation of signaling down-
stream of these extracellular cues by Cdk5 is suggested to play important
roles in axon growth and regeneration.
