AKT3 Recombinant Protein

The protein encoded by this gene is a member of the AKT, also called PKB, serine/threonine protein kinase family. AKT kinases are known to be regulators of cell signaling in response to insulin and growth factors. They are involved in a wide variety of biological processes including cell proliferation, differentiation, apoptosis, tumorigenesis, as well as glycogen synthesis and glucose uptake. This kinase has been shown to be stimulated by platelet-derived growth factor (PDGF), insulin, and insulin-like growth factor 1 (IGF1). Alternatively splice transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

Function: AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT3 is the least studied AKT isoform. It plays an important role in brain development and is crucial for the viability of malignant glioma cells. AKT3 isoform may also be the key molecule in up-regulation and down-regulation of MMP13 via IL13. Required for the coordination of mitochondrial biogenesis with growth factor-induced increases in cellular energy demands. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Ref.18 Ref.25

Catalytic activity: ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation: Two specific sites, one in the kinase domain (Thr-305) and the other in the C-terminal regulatory region (Ser-472), need to be phosphorylated for its full activation

By similarity. IGF-1 leads to the activation of AKT3, which may play a role in regulating cell survival.

Subunit structure: Interacts (via PH domain) with TCL1A; this enhances AKT3 phosphorylation and activation. Interacts with TRAF6. Ref.12 Ref.13 Ref.21

Subcellular location: Nucleus. Cytoplasm. Membrane; Peripheral membrane protein. Note: Membrane-associated after cell stimulation leading to its translocation. Ref.22

Tissue specificity: In adult tissues, it is highly expressed in brain, lung and kidney, but weakly in heart, testis and liver. In fetal tissues, it is highly expressed in heart, liver and brain and not at all in kidney.

Domain: Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PI3K) results in its targeting to the plasma membrane.

Post-translational modification: Phosphorylation on Thr-305 and Ser-472 is required for full activity

By similarity.Ubiquitinated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Ref.10 Ref.11O-GlcNAcylation at Thr-302 and Thr-309 inhibits activating phosphorylation at Thr-305 via disrupting the interaction between AKT and PDK1

By similarity.

Involvement in disease: AKT3 is a key modulator of several tumors like melanoma, glioma and ovarian cancer. Active AKT3 increases progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Promotes melanoma tumorigenesis by decreasing apoptosis. Plays a key role in the genesis of ovarian cancers through modulation of G2/M phase transition. With AKT2, plays a pivotal role in the biology of glioblastoma.Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) [MIM:603387]: A syndrome characterized by megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.30 Ref.31 Ref.32

Sequence similarities: Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.Contains 1 AGC-kinase C-terminal domain.Contains 1 PH domain.Contains 1 protein kinase domain.

Caution: In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain.

Biophysicochemical propertiesKinetic parameters:KM=87.9 µM for ATP (for purified and in vitro activated AKT3) Ref.16KM=12.4 µM for peptide substrate (for purified and in vitro activated AKT3)KM=118.7 µM for ATP (for recombinant myristoylated AKT3 expressed and immunoprecipitated from Rat-1 cells)KM=2.3 µM for peptide substrate (for recombinant myristoylated AKT3 expressed and immunoprecipitated from Rat-1 cells)