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enhance an axon regeneration response. Activation of AKT influences
activation of numerous downstream molecules including mTOR,
FAK, GSK-3
b
(glucose synthase kinase-3
b
), GS (glucose synthase),
PRAS40, Bad, FoxO1, and Myt1 to control key biological functions such
as metabolism, growth, cell cycle, and survival (
Cardoneetal.,1998;
Diehl, Cheng, Roussel, & Sherr, 1998; Hers, Vincent, & Tavare, 2011;
Okumuraetal.,2002;Sarbassov,Guertin,Ali,&Sabatini,2005;Wang
et al., 2012
). Among these downstream targets, mTOR and GSK
b
have
attracted considerable attention recently for their abilities to regulate
axon growth.
2.2.2 mTOR and axon regeneration
mTOR, also known as FK506 binding protein 12-rapamycin-associated
protein 1 (FRAP1), is an intracellular sensor that integrates signals regarding
cellular nutrient/energy/redox states to control protein synthesis and cell
growth. At the molecular level, activated mTOR exists in two structurally
and functionally distinct complexes in the cytoplasm. One such complex
contains raptor (regulatory-associated protein of TOR), a protein partner
for mTOR. This complex, known as mTORC1, is rapamycin-sensitive
and able to phosphorylate S6 kinase and 4EBP1 (
Fig. 7.1
). The other type
contains rictor (rapamycin-insensitive companion of TOR) and is associated
with cytoskeleton regulation (mTORC2) (
Oh & Jacinto, 2011
). Because of
its relevance to axon regeneration, only mTORC1 will be discussed in this
review (hereafter referred to simply as mTOR). The activity of this complex
is stimulated by insulin, mitogens, growth factors, and serum, and inhibited
by low nutrient levels, growth factor deprivation, and reductive stress (
Hay
& Sonenberg, 2004; Kim & Sabatini, 2004; Kim et al., 2002; Laplante &
Sabatini, 2012
). The regulation of mTOR activity in response to growth
factors is mediated mainly by the PI3K/AKT signaling pathway. AKT
activation leads to phosphorylation and inhibition of tuberous sclerosis
protein complex (TSC) which in turn results in subsequent engagement
of Ras homolog enriched in brain (Rheb) to activate mTOR (
Fig. 7.1
).
mTOR regulates global protein translation and ribosome biogenesis
through phosphorylation of different substrates, which are involved in
the initiation of cap-dependent protein translation, a rate-limiting step
of protein synthesis (
Ma & Blenis, 2009
). Deletion or functional
mutation of PTEN results in hyperactivation of AKT/mTOR, and
subsequentlyleadstoanincreaseincellgrowthcapacity(
Kwon et al.,
2003; Liu, Zhou, Reske, & Shen, 2008
). In mouse retinae, mTOR
