RAC-alpha serine/threonine kinases (AKTs) are crucial
mediators of various cellular process, such as apoptosis, regulation of cell cycle,
protein synthesis and regulation of metabolism. The activity of
AKT is modulated by various proteins, including
Phosphoinositide-dependent kinase 1 (PDK), phosphotases
PTEN, PP2A, and heat-shock
PI3K converts phosphatidylinositol 4,5-biphosphate
(PI(4,5)P2) to phosphatidylinositol
3,4,5-triphosphate (PI(3,4,5)P3), which is
secondary messenger involved the in regulation of various process .
PI(3,4,5)P3 associates with the inner lipid
bilayer of the plasma membrane and promotesthe recruitment of proteins with pleckstrin
homology (PH) domains such as AKT and
PDK. Upon binding to the membrane
AKT and PDK became active.
Notably, translocation of AKT to the plasma membrane also
facilitates its phosphorylation by PDK
AKT activity can be inhibited indirectly though the t
phosphatase PTEN that cleaves the 3' phosphate from
PI(3,4,5)P3 to generate
therefore, acts to decrease levels of PI(3,4,5)P3
causing an antagonistic effect of AKT-inducedcell survival
The phosphatase PP2A dephosphorylates and inhibits
AKT directly and this is counteracted by
Hsp90. Hsp90 forms a complex with
AKT and prevents PP2A-mediated
dephosphorylation. Hsp90 plays an important role in
maintaining AKT kinase activity .
Activated AKT prevents cells from undergoing apoptosis by
inhibiting proapoptotic proteins BCL2-associated agonist of cell death
(BAD) and Caspase-9 . AKT induces phosphorylation of BAD,
preventing BAD from
binding with anti-apoptotic factor BCL2-like 1
(BCL-X) therby reducing antiapoptotic events .
AKT can interfere with cell death via a member of the
forkhead family of transcription factors (e.g., Forkhead box O3
(FOXO3A), which is a direct target for phosphorylation by
AKT). FOXO3A has been
implicated in the expression of the FAS ligand (FasL) and
the Bcl-2 interacting mediator of cell death (Bim), which
can induce cell death. Upon phosphorylation by AKT,
FOXO3A is retained in the cytosol preventing transcriptional
regulation and expression of FasL and
Bim in the nuclease, allowing the cell survival .
AKT also regulates the activity of other transcription
factors, such as nuclear factor-kappaB (NF-kB), Tumor
protein p53 (p53), c-Myc. AKT
phosphorilates and activates I-kB kinase (IKK), that
regulate the activity of the NF-kB transcription factor.
When bound to its cytosolic inhibitor I-kB,
NF-kB is inactive. Upon phosphorylation of
I-kB by IKK, the inhibitor is
degraded, allowing NF-kB to move to the nucleus and activate
the transcription of antiapoptotic proteins .
AKT phosphorylates ubiquitin-protein ligase E3 Mdm2 p53
binding protein homolog (MDM2) that results in its
translocation into the nucleus where it binds to transcription factor
p53. p53 mediates apoptosis
through transactivation of apoptotic activator BAX . MDM2 interacts with the p53,
inhibits its transcriptional activity and targets it for degradation by
the proteasome .
AKT affects the cell cycle progression by regulating the
Cyclin D function. This is accomplished by phosphorylation
of Cyclin-dependent kinase inhibitor 1A (p21/WAF1) by
AKT. This result to cytoplasmic localization of
p21/WAF1, thereby preventing its function in the nucleus. In
the nucleous, the protein p21/WAF1 interacts with and
inhibits the essential DNA replication factor, proliferating-cell nuclear antigen
and PCNA forms complex with
Cyclin D .
Another target for AKT is
Glycogen synthase kinase 3 (GSK3), which
negativly regulates glycogen synthesis and cell cycle progression via inhibitory
phosphorylation of glycogen synthase and transcription factors c-Myc
and Cyclin D, respectively.
Additionally, FOXO3A has been implicated in expression of
the Cyclin-dependent kinase inhibitor 1B (P27KIP1), which
binds with and inhibits Cyclin D .
The activation of AKT results in the stimulation of
protein synthesis via activation of Ribosomal protein S6 kinase
(p70S6K). The activation of
p70S6K by AKT occurs via direct
and indirect mechanisms. The indirect process is mediated by FKBP-rapamycin associated
protein (FRAP1). In absence of
Tuberin via the small GTPase
Rheb inhibits FRAP1, allowing
the activation of P70S6K the
leads to multiple phosphorylation events of 40S ribosomal protein S6
(RPS6) to trigger protein synthesis .
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