Molecule Information

General Information of the Molecule (ID: Mol00011)

• Name: RAC-beta serine/threonine-protein kinase (AKT2) ,Homo sapiens
• Synonyms: Protein kinase Akt-2; Protein kinase B beta; PKB beta; RAC-PK-beta
• Molecule Type: Protein
• Gene Name: AKT2
• Gene ID: 208
• Location: chr19:40230317-40285536[-]
• Sequence:
  MNEVSVIKEGWLHKRGEYIKTWRPRYFLLKSDGSFIGYKERPEAPDQTLPPLNNFSVAEC
  QLMKTERPRPNTFVIRCLQWTTVIERTFHVDSPDEREEWMRAIQMVANSLKQRAPGEDPM
  DYKCGSPSDSSTTEEMEVAVSKARAKVTMNDFDYLKLLGKGTFGKVILVREKATGRYYAM
  KILRKEVIIAKDEVAHTVTESRVLQNTRHPFLTALKYAFQTHDRLCFVMEYANGGELFFH
  LSRERVFTEERARFYGAEIVSALEYLHSRDVVYRDIKLENLMLDKDGHIKITDFGLCKEG
  ISDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHERLFE
  LILMEEIRFPRTLSPEAKSLLAGLLKKDPKQRLGGGPSDAKEVMEHRFFLSINWQDVVQK
  KLLPPFKPQVTSEVDTRYFDDEFTAQSITITPPDRYDSLGLLELDQRTHFPQFSYSASIR
  E
• Function: AKT2 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. AKT is responsible of the regulation of 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 regulates also 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 regulates also 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 I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development.; FUNCTION: One of the few specific substrates of AKT2 identified recently is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsible of the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr-343'.
• Uniprot ID: AKT2_HUMAN
• Ensembl ID: ENSG00000105221
• HGNC ID: HGNC:392

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Osteosarcoma [1]

• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Caspase-3 Activity Assay
• Mechanism Description: miR200c regulates tumor growth and chemosensitivity to cisplatin in osteosarcoma by targeting AkT2 and inhibiting the activity of cell proliferation and cell migration.

Disease Class: Gastric cancer [2]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The expression of miR-29b was significantly upregualted by cisplatin treatment,while its target gene AkT2 was downregulated. The up-regulation of miR-29b (+) the sensitivity of gastric cancer cells to cisplatin,while the knock-down of miR-29b (+) the cisplatin resistance. Rescue experiments demonstrated that the miR-29b might regulate cisplatin resistance of gastric cancer cell by targeting PI3k/Akt pathway. The expressions of the other two members of miR-29 family, miR-29a/c, were promoted by cisplatin treatment,but they had no significant effect on gastric cancer cell's resistance to cisplatin.

Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colon cancer [3]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Regulation; hsa04151
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The tumor suppressive role of miR-203 was mediated by negatively regulating Akt2 protein expression through mRNA degradation. The inhibition of Akt2 activity downregulated the protein expression of its downstream molecules involved in chemoresistance, such as MTDH and HSP90 genes.

Preclinical Drug(s) 1 drug(s) in total

Allosteric AKT inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Allosteric AKT inhibitors
• Molecule Alteration: Copy number gain; .
• Experimental Note: Revealed Based on the Cell Line Data

Disease Class: Solid tumour/cancer [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Allosteric AKT inhibitors
• Molecule Alteration: Copy number gain; .
• Experimental Note: Revealed Based on the Cell Line Data

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Gastric cancer [ICD-11: 2B72]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Gastric tissue
• The Specified Disease: Gastric cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.03E-01; Fold-change: -4.15E-02; Z-score: -6.94E-02
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.97E-04; Fold-change: 1.63E-01; Z-score: 9.39E-01

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.96E-08; Fold-change: 1.10E-01; Z-score: 4.46E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.80E-23; Fold-change: 2.16E-01; Z-score: 1.03E+00

References

• Ref 1: MiR-200c regulates tumor growth and chemosensitivity to cisplatin in osteosarcoma by targeting AKT2. Sci Rep. 2017 Oct 19;7(1):13598. doi: 10.1038/s41598-017-14088-3.
• Ref 2: [miR-29b Reduces Cisplatin Resistance of Gastric Cancer Cell by Targeting PI3K/Akt Pathway]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2015 Oct;37(5):514-9. doi: 10.3881/j.issn.1000-503X.2015.05.005.
• Ref 3: miR-203 reverses chemoresistance in p53-mutated colon cancer cells through downregulation of Akt2 expression. Cancer Lett. 2011 May 1;304(1):52-9. doi: 10.1016/j.canlet.2011.02.003. Epub 2011 Feb 26.
• Ref 4: STATISTICS/DATA TYPE - iGMDR.