Biology Reference
In-Depth Information
2. PTEN: A NEGATIVE REGULATOR OF CELL AND AXON
GROWTH
Activationof phosphoinositide3-kinase (PI3K) in response toa varietyof
extracelluar stimuli including growth factors, mitogens, and hormones regu-
lates key biological processes including cell growth, proliferation, survival,
andmotility. This lipidkinasephosphorylates converts the lipid secondmessen-
ger phosphatidylinositol (4,5) bisphosphate (PIP
2
) into phosphatidylinositol
(3,4,5) trisphosphate (PIP
3
), which in turn recruits and activates
phosphatidylinositol-dependent kinase 1/2 (PDK1/2), resulting in the activa-
tion of AKT (
Song,Ouyang,&Bao, 2005; Vogt,Gymnopoulos,&Hart, 2009
)
(
Fig. 7.1
). On the other side, PTEN functions both as a dual specificity protein
phosphatase and lipid phosphatase. Although it can dephosphorylate protein
substrates such as FAK (focal adhesion kinase), PTEN's predominant
enzymatic activity seems to be the dephosphorylation of the 3
0
phosphate of
the inositol ring in PIP
3
, resulting in the biphosphate product PIP
2
(PtdIns
(4,5)P
2
)
Di Cristofano & Pandolfi, 2000; Leslie & Downes, 2004;
Tamguney & Stokoe, 2007
)(
Fig. 7.1
). Thus, inactivation of PTEN results in
the accumulation of PIP
3
and hyperactivation of AKT. As PI3K/AKT signals
control the cell metabolism, growth, proliferation, and survival, deregulation
PTEN has been closely associated with development of certain tumor cells
(
Carracedo, Alimonti, & Pandolfi, 2011; Di Cristofano & Pandolfi, 2000
). In
the nervous system, neuron-specific loss of PTEN during mouse development
causes high levels of phosphorylated AKT and a gradual increase in soma size
without causing abnormal proliferation (
Kwon, Zhu, Zhang, & Baker, 2003;
Kwon et al., 2001
). In the mature CNS, PTEN depletion in neurons has
been shown to prevent apoptotic cell death in acute and degenerative injury
models (
Kirby et al., 2011; Li et al., 2009; Park et al., 2008; Shi et al., 2011
).
In addition to its role in cell growth and survival, recent studies point to the
importance of PTEN in regulating axon growth/regeneration. Because
multiple downstream effectors of PTEN operate in both neuronal soma and
axon terminal, PTEN is ideally positioned to coordinate different steps of
axon growth during development and injury-induced axon regeneration.
2.1. PTEN is an intrinsic blocker of axon regrowth
Several studies have indicated PTEN as a factor within neurons that impede
axon regeneration. These studies have shown that pharmacological or
genetic inactivation of PTEN in neurons enhances axon regeneration both
