Akt Signaling Pathway

Click on one of the cellular processes below to highlight the molecules involved and how they are regulated by Akt signaling.

Stimulation
Stimulation
RTK
RTK
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Ras
Ras
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Adaptor
Adaptor
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p110
p110
p85
p85
p110
p110
p85
p85
PI 3-Kinase
PI 3-Kinase
PI 3-K
PI 3-K
PIP2
PIP2
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PIP3
PIP3
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PDK-1
PDK-1
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mTORC2
mTORC2
Akt
Akt
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PTEN
PTEN
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PIP2
PIP2
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PIP3
PIP3
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TSC2
TSC2
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TSC1
TSC1
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Rheb
Rheb
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mTORC1
mTORC1
p70 S6
Kinase
p70 S6
Kinase
Beclin 1
Beclin 1
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PIK3R4
PIK3R4
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hVps34
hVps34
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ULK
Complex
ULK
Complex
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4EBP1
4EBP1
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PDCD4
PDCD4
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eIF4B
eIF4B
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eIF4E
eIF4E
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eIF4G
eIF4G
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eIF4A
eIF4A
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p27/Kip1
p27/Kip1
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p27/Kip1
p27/Kip1
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p27/Kip1
p27/Kip1
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MDM2
MDM2
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p53
p53
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p53
p53
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GSK-3
GSK-3
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Myc
Myc
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E2F
E2F
p21/CIP1
p21/CIP1
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CDKs
CDKs
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CDKs
CDKs
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Proteasome
Proteasome
FoxO
FoxO
FoxO
FoxO
p21/CIP1
p21/CIP1
p21/CIP1
p21/CIP1
BIM
BIM
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Pro-Caspase-3
Pro-Caspase-3
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Bcl-xL
Bcl-xL
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Bad
Bad
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Autophagy

Autophagy

Translation
Initiation

Translation
Initiation

Cell Cycle
Progression

Cell Cycle
Progression

Apoptosis

Apoptosis

Survival

Survival

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p53
p53
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Overview of the Akt Signaling Pathway

PI 3-Kinase can be activated by numerous stimuli, including mitogen-stimulated receptor tyrosine kinases (RTKs). The PI 3-Kinase p85 regulatory subunit interacts with RTKs either directly via its Src-homology 2 (SH2) domains or indirectly via an adaptor protein, such as GAB. Activated PI 3-Kinase then phosphorylates phosphatidylinositol (4,5)-bisphosphate (PIP2), resulting in the formation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) at the plasma membrane. PIP3 recruits Akt and PDK1 to the plasma membrane where PDK1 activates Akt via phosphorylation at Thr308. Akt activation is opposed by the phosphatase PTEN, which dephosphorylates PIP3 to PIP2 and prevents Akt and PDK1 recruitment to the plasma membrane. Additionally, Akt is phosphorylated at Ser473 by mammalian Target of Rapamycin complex 2 (mTORC2) for maximal activation. Activated Akt subsequently impacts many cellular processes, including autophagy, protein synthesis, cell cycle progression, and cellular survival. It suppresses autophagy both directly, via phosphorylation of Beclin 1, and indirectly via the activation of mTORC1. Akt inhibits TSC2 via phosphorylation at Ser939/981, which allows Rheb to activate mTORC1. mTORC1 then negatively regulates ULK1 via phosphorylation, resulting in autophagy inhibition. Activation of mTORC1 downstream of Akt also increases protein synthesis. mTORC1 promotes translation initiation both by activation of p70 S6 Kinase and by inhibition of the translational suppressor 4EBP1. Akt promotes cell cycle progression through the regulation of transcription factors and cell cycle regulators. The p53 and FoxO transcription factors are negatively regulated via Akt-activated MDM2 (Ser186) and direct phosphorylation by Akt, respectively. Furthermore, Akt indirectly activates Myc and E2F transcription factors by relieving their inhibition by GSK-3 and p21/CIP1, respectively. The negative cell cycle regulators p21/CIP1 and p27/Kip1 are inhibited by Akt at the level of transcription (FoxO inhibition) and subcellular localization (cytoplasmic retention by direct phosphorylation). Finally, activated Akt promotes cellular survival via inhibition of the pro-apoptotic proteins BIM and Bad and the cytoplasmic retention of p21/CIP1. BIM and Bad inhibit Bcl-xL, a pro-survival protein that blocks Cytochrome c release and subsequent apoptosis. Akt directly inhibits Bad via phosphorylation (Ser136) and indirectly inhibits BIM via downregulation of FoxO-dependent BIM transcription. Cytoplasmic p21/CIP1 inhibits apoptosis via binding Pro-Caspase-3 and preventing its cleavage to active Caspase-3.

To learn more, please visit our Akt Pathway Research Area.

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