: 14-3-3 : activation of Akt1 : Akt1 action : Bad : Bad/Bcl-XL : Bcl-XL : c-Akt : caspase 9 : cell survival pathways : forkhead : growth factors : hTERT : IkB kinases : IKKα : ILK : integrin : NF-κβ : surface receptors : PDK1 : PI3K : PIP control : PTEN : v-akt : Wortmannin :
Specific protein kinases transfer a phosphate group from a donor such as ATP to amino acid acceptors in proteins, while protein phosphatases remove the phosphate groups that have been attached by protein kinases. Proto-oncogenes participate in a variety of normal cellular functions, but have the potential to tranform into cellular oncogenes when mutated. Proto-oncogenes normally function in the various signal transduction cascades that regulate cell growth, proliferation and differentiation. Cellular proto-oncogenes resident in transforming retroviruses are designated as c- (cellular origin) as opposed to v- (retroviral origin).
Akt1 activation requires PDK1 phosphorylation of Thr308 in the activation domain and is dependent on the products of phosphatidylinositol (PI) 3-kinase (PI3K), phosphatidylinositol 3,4 bisphosphate (PIP2) and phosphatidylinositol 3,4,5 trisphosphate (PIP3). When activated, Akt exerts anti-apoptosis effects through phosphorylation of substrates that directly regulate the apoptosis machinery (Bad or caspase 9), or phosphorylation of substrates that indirectly inhibit apoptosis (human telomerase reverse transcriptase subunit (hTERT), forkhead transcription family members, or IkB kinases). Akt promotes survival in vitro when cells are exposed to different apoptotic stimuli such as growth factor deprivation, UV irradiation, matrix detachment, cell cycle discordance, DNA damage, and administration of anti-Fas antibody, TGF-β, glutamate, or bile acids.
Akt is the cellular homologue of the product of the v-akt oncogene and has 3 isoforms, Akt1, 2, and 3 (or PKB-α, -β, and -γ). Akt is activated by many growth factors, including IGF-I, EGF, βFGF, insulin, interleukin-3, interleukin-6, heregulin, and VEGF. Full activity of all three isoforms requires phosphorylation of both a site in the activation domain and another site in the C-terminal hydrophobic motif.
Many cell surface receptors induce second messengers that activate phosphatidylinositide-3-OH kinase (PI3K). Because Akt is located downstream of PI3K Akt functions as part of a wortmannin-sensitive signaling pathway. PI3K generates phosphorylated phosphatidylinositides in the cell membrane, which bind to the amino-terminal pleckstrin homology (PH) domain of Akt. The phosphatidylinositides, PI-3,4-P2 and PI-3,4,5-P3 also activate phosphoinositide-dependent kinase-1 (PDK1) which phosphorylates Thr308 of membrane-bound Akt. The Ser473 is phosphorylated by integrin-linked kinase (ILK).
Activated Akt promotes cell survival via two distinct pathways:
1) Akt inhibits apoptosis by phosphorylating the Bad component in the Bad/Bcl-XL complex. When phosphorylated, Bad binds to protein 14-3-3, leading to dissociation of the Bad/Bcl-XL complex and permitting cell survival.
2) Alternatively, Akt activates IKK-α, which ultimately leads to NF-κβ activation and cell survival.
Cellular levels of PIP2 and PIP3 are controlled by the tumor suppressor, dual-phosphatase PTEN, which dephosphorylates PIP2 and PIP3 at the 3' position.
Wortmannin is a fungal metabolite that is a specific inhibitor of PI3Ks, though it can also inhibit mTOR, DNA-PK, some phosphatidylinositol 4-kinases, myosin light chain kinase (MLCK) and mitogen-activated protein kinase (MAPK).
: 14-3-3 : activation of Akt1 : Akt1 action סּ apoptosis : Bad : Bad/Bcl-XL : Bcl-XL סּ Bcl-2 : c-Akt : caspase 9 סּ caspases : cell survival pathways ₪ cellular survival סּ death receptor : forkhead : growth factors ~ growth factors : hTERT : IkB kinases : IKKα : ILK : integrin ~ integrins : NF-κβ : surface receptors סּ receptor proteins : PDK1 ♦ PDK1 : PI3K ♦ PI3K : PIP control : PTEN ♦ PTEN סּ receptor proteins ~ second messengers סּ signal transduction : v-akt : Wortmannin :
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