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Details on Person UniProt:P31751-1 AKT2
| Class:Id | ReferenceIsoform:8977285 |
|---|---|
| _chainChangeLog | chain:1-481 added on Fri February 17 2017 |
| _displayName | UniProt:P31751-1 AKT2 |
| _timestamp | 2025-05-21 21:22:49 |
| chain | chain:1-481 |
| checksum | B18C87A7246BFB24 |
| comment | FUNCTION Serine/threonine kinase closely related to AKT1 and AKT3. All 3 enzymes, AKT1, AKT2 and AKT3, are collectively known as AKT kinase. AKT regulates many processes including metabolism, proliferation, cell survival, growth and angiogenesis, through the phosphorylation of a range of downstream substrates. Over 100 substrates have been reported so far, although for most of them, the precise AKT kinase catalyzing the reaction was not specified. AKT regulates glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT also regulates the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT also regulates cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor 1 (IGF1). AKT mediates the antiapoptotic effects of IGF1. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development (PubMed:21432781, PubMed:21620960). In response to lysophosphatidic acid stimulation, inhibits the ciliogenesis cascade. In this context, phosphorylates WDR44, hence stabilizing its interaction with Rab11 and preventing the formation of the ciliogenic Rab11-FIP3-RAB3IP complex. Also phosphorylates RAB3IP/Rabin8, thus may affect RAB3IP guanine nucleotide exchange factor (GEF) activity toward Rab8, which is important for cilia growth (PubMed:31204173). Phosphorylates PKP1, facilitating its interaction with YWHAG and translocation to the nucleus, ultimately resulting in a reduction in keratinocyte intercellular adhesion (By similarity). Phosphorylation of PKP1 increases PKP1 protein stability, translocation to the cytoplasm away from desmosome plaques and PKP1-driven cap-dependent translation (PubMed:23444369).FUNCTION Several AKT2-specific substrates have been identified, including ANKRD2, C2CD5, CLK2 and PITX2. May play a role in myoblast differentiation. In this context, may act through PITX2 phosphorylation. Unphosphorylated PITX2 associates with an ELAVL1/HuR-containing complex, which stabilizes CCND1 cyclin mRNA, ensuring cell proliferation. Phosphorylation by AKT2 impairs this association, leading to CCND1 mRNA destabilization and progression towards differentiation (By similarity). Also involved in the negative regulation of myogenesis in response to stress conditions. In this context, acts by phosphorylating ANKRD2 (By similarity). May also be a key regulator of glucose uptake. Regulates insulin-stimulated glucose transport by the increase of glucose transporter GLUT4 translocation from intracellular stores to the plasma membrane. In this context, acts by phosphorylating C2CD5/CDP138 on 'Ser-197' in insulin-stimulated adipocytes (By similarity). Through the phosphorylation of CLK2 on 'Thr-343', involved in insulin-regulated suppression of hepatic gluconeogenesis (By similarity).CATALYTIC ACTIVITY L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+)CATALYTIC ACTIVITY L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+)ACTIVITY REGULATION Phosphorylation at Thr-309 (in the kinase domain) and Ser-474 (in the C-terminal regulatory region) is required for full activation (PubMed:18800763, PubMed:19179070). In adipocytes and hepatocytes, the activation is induced by insulin (By similarity). Aminofurazans, such as 4-[2-(4-amino-2,5-dihydro-1,2,5-oxadiazol-3-yl)-6-{[(1S)-3-amino-1-phenylpropyl]oxy}-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol (compound 32), are potent AKT2 inhibitors (PubMed:19179070). AKT2 phosphorylation of PKP1 is induced by insulin (PubMed:23444369).BIOPHYSICOCHEMICAL PROPERTIES Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via PH domain) with MTCP1, TCL1A and TCL1B; this interaction may facilitate AKT2 oligomerization and phosphorylation, hence increasing kinase activity (PubMed:10983986). Interacts with PHB2; this interaction may be important for myogenic differentiation (By similarity). Interacts (when phosphorylated) with CLIP3/ClipR-59; this interaction promotes AKT2 recruitment to the plasma membrane (By similarity). Interacts with WDFY2/ProF (via WD repeats 1-3) (PubMed:16792529).INTERACTION Through binding of the N-terminal PH domain to phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) or phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2), recruited to the plasma membrane. Cell membrane recruitment is facilitated by interaction with CLIP3. Colocalizes with WDFY2 in early endosomes (By similarity). Localizes within both nucleus and cytoplasm in proliferative primary myoblasts and mostly within the nucleus of differentiated primary myoblasts (PubMed:17565718).ALTERNATIVE PRODUCTS Widely expressed. Expressed in myoblasts (PubMed:17565718).DEVELOPMENTAL STAGE Up-regulated in in vitro differentiating primary myoblasts.DOMAIN Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activation results in AKT2 recruitment to the plasma membrane, exposition of a pair of serine and threonine residues for phosphorylation by membrane-associated PDPK1/PDK1 and activation.PTM Phosphorylation on Thr-309 and Ser-474 is required for full activity (PubMed:12086620, PubMed:12434148, PubMed:15890450, PubMed:20059950). Phosphorylation of the activation loop at Thr-309 by PDPK1/PDK1 is a prerequisite for full activation (By similarity). Phosphorylated and activated by PDPK1/PDK1 in the presence of phosphatidylinositol 3,4,5-trisphosphate (PubMed:9512493). Phosphorylation by mTORC2 in response to growth factors plays a key role in AKT1 activation: mTORC2 phosphorylates different sites depending on the context, such as Ser-474 or Ser-478, thereby facilitating subsequent phosphorylation of the activation loop by PDPK1/PDK1 (By similarity).PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6 catalyzes 'Lys-63'-linked AKT2 ubiquitination; this modification may be important for AKT2 recruitment to the plasma membrane and for AKT2 activating phosphorylation (PubMed:19713527). When phosphorylated, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3 in the nucleus, leading to its degradation by the proteasome (PubMed:20059950).PTM O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via the disruption of the interaction between AKT and PDPK1/PDK1.DISEASE Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. May play a role in glioblastoma cell survival (PubMed:20167810).DISEASE Disease susceptibility is associated with variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION In light of strong identity in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. However, it is now known that each AKT may display 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. |
| created | [InstanceEdit:8964659] Weiser, JD |
| description | recommendedName: RAC-beta serine/threonine-protein kinase ecNumber evidence="12 14 15 26 28"2.7.11.1 alternativeName: Protein kinase Akt-2 alternativeName: Protein kinase B beta shortName evidence="33"PKB beta alternativeName: fullName evidence="30"RAC protein kinase beta shortName: RAC-PK-beta |
| geneName | AKT2 |
| identifier | P31751 |
| isoformParent | |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Alternative splicing Apoptosis ATP-binding Carbohydrate metabolism Cell membrane Cytoplasm Developmental protein Diabetes mellitus Disease variant Disulfide bond Endosome Glucose metabolism Glycogen biosynthesis Glycogen metabolism Glycoprotein Kinase Manganese Membrane Metal-binding Nucleotide-binding Nucleus Phosphoprotein Proteomics identification Proto-oncogene Reference proteome Serine/threonine-protein kinase Sugar transport Transferase Translation regulation Transport Ubl conjugation |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9948485] Weiser, Joel, 2025-05-21 |
| name | AKT2 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8992881] ENSEMBL:ENSG00000105221 AKT2 [Homo sapiens] |
| secondaryIdentifier | AKT2_HUMAN B2RBD8 Q05BV0 Q0VAN0 Q0VAN1 Q68GC0 |
| sequenceLength | 481 |
| species | [Species:48887] Homo sapiens |
| variantIdentifier | P31751-1 |
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No pathways have been reviewed or authored by UniProt:P31751-1 AKT2 (8977285)
