Biology Reference
In-Depth Information
A
Extrinsic factors and receptor regulation
Promoting factors
Inhibitory factors
Other
Growth factors
Guidance
cues
Myelin-associated
inhibitors
CSPGs
Neurotrophins
Cytokines
Trk
receptors
Cytokine
receptors
Guidance
receptors
myelin
receptors
CSPG
receptors
Cell body
Axon shaft
Growth cone
B
C
Gene expression
Cytoskeletal remodeling
P
RTKs
Cytokine receptors
MAPs
(DCX, MAP1B, Tau)
P
SIRT2
PI3K
Cdk5
JAK2
Microtubule
Ac
PTEN
Axin
Cdk5
P
SOCS3
Akt
P
GSK3
β
APC
Cdh1
CRMP2
P
P
STAT3
mTOR
Cdk5
P
Cdc42
Actin
S6K1
P
4E-BP
P
GEFs/GAPs
p53
SnoN
Id2
Cdk5
S6
Ub
Ub
Ub
Rac1
Pak1
Ub
Ub
Ub
Ribosome
elF-4E
P
mRNA
p27
kip1
RhoA
WAVE1
P
P
P
STAT3
p53
DNA
Figure 5.1 Signaling pathways mediated by Cdk5 are implicated in various cellular
processes that are critical for the axon regeneration. (A) Axon regeneration is regulated
by positive and negative signaling cascades triggered by extrinsic factors. While neuro-
trophins, cytokines, and other growth factors stimulate sprouting or regeneration of
injured axons, other extracellular factors including repulsive guidance cues, myelin-
associated inhibitors, and CSPGs prevent axon regeneration. Cdk5 has been suggested
to modulate downstream signaling of specific neurotrophins and guidance cues during
axon development. Notably, TrkB, the cognate receptor of BDNF, is directly phosphor-
ylated by Cdk5, implicating Cdk5 in BDNF-induced neurite growth. (B) Regulators of
transcriptional and translational programs determine intrinsic growth ability of devel-
oping or injured axons. Genetic deletion of either SOCS3 or PTEN dramatically enhances
axon regeneration after CNS injury, underscoring the pivotal roles of transcriptional and
translational machineries in axon regeneration. Cdk5 is implicated in safeguarding the
expression of regeneration-associated genes through phosphorylation of various tran-
scriptional factors (STAT3, p53) and translational regulators (S6K1). On the other hand,
Cdk5 potentially prevents APC/Cdh1-mediated protein degradation by dissociating
Cdh1 from APC during axon growth and repair. (C) Efficient axon growth and regener-
ation requires coordinated rearrangement of microtubule and actin cytoskeleton.
Cdk5 is involved in enabling efficient microtubule assembly and stabilization through
Axin-mediated inhibition of GSK3
b
. In addition, Cdk5-mediated phosphorylation of
SIRT2 maintains acetylation of
a
-tubulin, suggesting another mechanism by which
microtubules are stabilized by Cdk5. Further, Cdk5 regulates actin dynamics through
modulation of Rho GTPases. See text for abbreviations and details.
