Biology Reference
In-Depth Information
Growth
factor
PI3K
PIP3
PIP2
PDK
PP
PTEN
p27
Assembly and
organization of
cytoskeletons in
the axon
terminals
TSC1
TSC2
Bad
AKT
GSK3
Rheb
mTOR
rictor
mTOR
mTOR
raptor
Increase in
protein synthesis
capacity
S6K
4EBP
eIF4E
Growth cone
formation and axon
extension
Forkhead
STAT3
CREB
NFAT
Figure 7.1 PTEN pathway and axon growth inhibition. Activated PI3K catalyzes conver-
sion of membrane-bound lipid secondary messenger phosphatidylinositol (4,5)
bisphosphate (PIP2) into phosphatidylinositol (3,4,5) trisphosphate (PIP3). This reaction
is antagonized by PTEN, which maintains a low level of PIP3 in the membrane. Upon
activation of receptor tyrosine kinase (i.e., by growth factors), PI3K is activated and
PIP3 accumulates. Cytoplasmic PDK is subsequently recruited and activated, which in turn
activates AKT. Activated AKT inhibits the TSC1/2 complex, thereby releases Rheb from in-
hibition and activatesmTOR. ActivatedmTOR exists in two forms. The rapamycin-sensitive
mTOR/raptor complex regulates global translation by activation of S6K, the kinase that
phosphorylates ribosomal protein S6 in the 40S subunit, and eIF4E, the general initiation
factor for 5
0
cap-dependent translation. Activated mTOR/raptor complex is also implicated
in upregulation of STAT3 transcriptional activity. Activated AKT regulates activation and
deactivation of many downstream targets including Forkhead, p27 and Bad to affect cell
cycle and apoptosis. Also regulated by PTEN/AKT pathways is the GSK3 which regulates
cytoskeletal dynamic andmicrotubule assembly, and transcription factors including NFAT
and CREB to facilitate axon growth
in the CNS and PNS. One of the early evidence supporting the inhibitory
role of PTEN involved an
in vivo
screen to identify factors that block axon
regeneration of retinal ganglion cells (RGCs; whose axons form the optic
nerve). Cre recombinase-mediated PTEN deletion in murine RGCs pro-
moted considerable axon regeneration after optic nerve injury (
Park
et al., 2008
). Further characterization of axon growth revealed that the axons
