Downstream Effects Akt/PKB signaling pathway

1 downstream effects

1.1 cell survival , apoptosis
1.2 lysosome biogenesis , autophagy
1.3 cell cycle progression
1.4 cell migration

downstream effects

once active, akt translocates plasma membrane cytosol , nucleus, many of substrates reside. akt regulates wide range of proteins phosphorylation. akt target substrates contain minimum consensus sequence r-x-r-x-x-[ser/thr]-hyd, hyd hydrophobic amino acid, although other factors such sub-cellular localisation , 3-dimensional structure important. phosphorylation akt can inhibitory or stimulatory, either suppressing or enhancing activity of target proteins.

cell survival , apoptosis

the substrates of akt involved in promoting cell survival or blocking apoptosis

the akt-pi3k pathway essential cell survival activated akt influences many factors involved in apoptosis, either transcription regulation or direct phosphorylation. in nucleus, akt inhibits transcription factors promote expression of cell death genes, , enhances transcription of anti-apoptotic genes. studied example forkhead family transcription factors (foxo/fh), of fkhr/foxo1, fkhrl1/foxo3 , afx/foxo4 directly phosphorylated akt. phosphorylation induces export cytosol sequestered 14-3-3 proteins , undergo degradation via ubiquitin-proteasome pathway.

akt positively regulates transcription factors allow expression of pro-survival genes. akt can phosphorylate , activate iκb kinase ikkα, causing degradation of iκb , nuclear translocation of nf-κb promotes expression of caspase inhibitors, c-myb , bcl-xl. promoting cell survival, camp response element binding protein (creb) phosphorylated akt @ ser133, stimulating recruitment of creb-binding protein (cbp) promoter of target genes, such bcl-2. akt has been shown phosphorylate murine double minute 2 (mdm2), key regulator of dna damage responses, @ ser166 , ser186. phosphorylation of mdm2 akt upregulates ubiquitin-ligase activity, therefore indirectly suppressing p53-mediated apoptosis. target of akt yes-associated protein (yap), phosphorylated @ ser127 leading 14-3-3 binding , cytosolic localisation. therefore, cannot co-activate p73-mediated apoptosis in response dna damage.

akt negatively regulates pro-apoptotic proteins direct phosphorylation. example, phosphorylation of bad, bcl-2 family member, on ser136 causes translocation mitochondrial membrane cytosol, sequestered 14-3-3 proteins. akt phosphorylates caspase-9 on ser196, preventing caspase cascade leading cell death. akt phosphorylates map kinase kinase kinases (mapkkk) upstream of stress-activated protein kinase (sapk) pathway. phosphorylation of apoptosis signal-regulating kinase 1 (ask1) on ser83 , mixed lineage kinase 3 (mlk3) on ser674 inhibits activity , prevents map kinase induced apoptosis.

lysosome biogenesis , autophagy

akt regulates tfeb, master controller of lysosomal biogenesis, direct phosphorylation of tfeb @ serine 467. phosphorylated tfeb excluded nucleus , less active. pharmacological inhibition of akt promotes nuclear translocation of tfeb, lysosomal biogenesis , autophagy.

cell cycle progression

the effects of akt activation on cell cycle progression

akt promotes g1-s phase cell cycle progression phosphorylating , inactivating glycogen synthase kinase 3 (gsk-3) @ ser9. prevents phosphorylation , degradation of cyclin d1. therefore, akt promotes g1 phase progression in positive feedback loop. akt promotes cyclin d1 translation via indirect activation of mtor. mtor increases translation of cyclin d1 activating ribosomal protein s6k, , inhibiting eukaryotic translation initiation factor 4e-binding protein (4e-bp), increasing eif4e activity.

akt both indirectly , directly regulates cyclin-dependent kinase (cdk) inhibitors p21 , p27 , allowing cell cycle progression. akt phosphorylates p27 @ thr157, preventing nuclear import. in addition, akt phosphorylates thr145 , ser146 of p21, preventing pcna binding , decreasing stability. akt phosphorylation of foxo transcription factors affects cell cycle, inhibitory phosphorylation of foxo4 (also named afx) prevents p27 gene expression.

cell migration

akt phosphorylates many proteins involved in polymerisation , stabilisation of actin cytoskeleton. in normal cells, can either increase stability of cytoskeleton components or promote migration via remodelling. examples listed below:

actin filaments - akt phosphorylates actin directly
akt phosphorylation enhancer (ape), named girdin - phosphorylated @ ser1416 causing translocation leading edge of filaments, essential migration
sodium-hydrogen exchanger 1 (nhe1) - phosphorylated @ ser648, promoting cytoskeletal rearrangements , migration
filamin - phosphorylated @ ser2152, promoting caveolin-1 mediated cell migration
kank - kidney ankyrin repeat-containing protein - negatively regulating rhoa activation , cell migration in response insulin , egf
tuberous sclerosis complex 2 (tsc2) - akt1 destabilises rho gtpase, inhibits f-actin assembly , reduces cell migration
palladin - akt1 phosphorylates actin-binding protein @ ser507, disrupting cross-linking of f-actin bundles

akt promotes cell migration interacting other cytoskeleton components. type iii intermediate filament vimentin phosphorylated akt1 @ ser39, preventing degradation. in normal cells, maintains tissue stability. s-phase kinase-associated protein 2 (skp2) - ser72 phosphorylation enhances e3 ligase activity , cytosolic localisation, promoting cell motility. akt phosphorylates gsk3 beta, indirectly activating microtubule binding protein adenomatous polyposis coli (apc). endothelial nitric oxide synthase (enos) phosphorylated @ ser1177, leading no synthesis , endothelial cell migration. in addition, pro-migratory gtpase-activating protein rhogap22 phosphorylated @ ser16.