Molecule Information

General Information of the Molecule (ID: Mol04358)

• Name: RAC-alpha serine/threonine-protein kinase (AKT1) ,Homo sapiens
• Synonyms: Protein kinase B; Protein kinase B alpha; Proto-oncogene c-Akt; RAC-PK-alpha
• Molecule Type: Protein
• Gene Name: AKT1
• Gene ID: 207
• Sequence:
  MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQC
  QLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMD
  F RSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAM
  KI LKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFF
  HLS RERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLC
  KEGI KDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHE
  KLFEL ILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQ
  HVYEKK LSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFS
  YSASGTA
• Function: AKT1 is one of 3 closely related serine/threonine-proteinkinases called the AKT kinase, and which regulatemany processes including metabolism, proliferation, cell survival,growth and angiogenesis .This is mediated through serine and/or threonine phosphorylation of arange of downstream substrates .Over 100 substrate candidates have been reported so far, but for mostof them, no isoform specificity has been reported . AKT is responsibleof the regulation of glucose uptake by mediating insulin-inducedtranslocation of the SLC2A4/GLUT4 glucose transporter to the cellsurface . Phosphorylation of PTPN1 at 'Ser-50'negatively modulates its phosphatase activity preventingdephosphorylation of the insulin receptor and the attenuation ofinsulin signaling . Phosphorylation of TBC1D4 triggersthe binding of this effector to inhibitory 14-3-3 proteins, which isrequired for insulin-stimulated glucose transport .AKT also regulates the storage of glucose in the form of glycogen byphosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting ininhibition of its kinase activity . Phosphorylation ofGSK3 isoforms by AKT is also thought to be one mechanism by which cellproliferation is driven . AKT also regulates cellsurvival via the phosphorylation of MAP3K5 . Phosphorylation of 'Ser-83' decreases MAP3K5kinase activity stimulated by oxidative stress and thereby preventsapoptosis . AKT mediates insulin-stimulated proteinsynthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', therebyactivating the mTORC1 signaling pathway, and leading to bothphosphorylation of 4E-BP1 and in activation of RPS6KB1. Also regulates the mTORC1 signalingpathway by catalyzing phosphorylation of CASTOR1 and DEPDC5. AKT plays a role as key modulatorof the AKT-mTOR signaling pathway controlling the tempo of the processof newborn neurons integration during adult neurogenesis, includingcorrect neuron positioning, dendritic development and synapse formation. Part of a positive feedback loop of mTORC2 signalingby mediating phosphorylation of MAPKAP1/SIN1, promoting mTORC2activation . AKT is involved in the phosphorylation ofmembers of the FOXO 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 arephosphorylated on equivalent sites . AKT has animportant role in the regulation of NF-kappa-B-dependent genetranscription and positively regulates the activity of CREB1 -response element binding protein) . Thephosphorylation of CREB1 induces the binding of accessory proteins thatare necessary for the transcription of pro-survival genes such as BCL2and MCL1 . AKT phosphorylates 'Ser-454' on ATP citratelyase , thereby potentially regulating ACLY activity and fattyacid synthesis . Activates the 3B isoform of cyclicnucleotide phosphodiesterase via phosphorylation of 'Ser-273',resulting in reduced cyclic AMP levels and inhibition of lipolysis . Phosphorylates PIKFYVE on 'Ser-318', which results inincreased PIP-5 activity . The Rho GTPase-activatingprotein DLC1 is another substrate and its phosphorylation is implicatedin the regulation cell proliferation and cell growth .Signals downstream of phosphatidylinositol 3-kinase K) to mediatethe effects of various growth factors such as platelet-derived growthfactor , epidermal growth factor , insulin and insulin-likegrowth factor 1 . AKT mediatesthe antiapoptotic effects of IGF1 . Essential for theSPATA13-mediated regulation of cell migration and adhesion assembly anddisassembly . May be involved in the regulation of theplacental development . Phosphorylates STK4/MST1 at'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity,nuclear translocation, autophosphorylation and ability to phosphorylateFOXO3 . Phosphorylates STK3/MST2 at 'Thr-117' and'Thr-384' leading to inhibition of its: cleavage, kinase activity,autophosphorylation at Thr-180, binding to RASSF1 and nucleartranslocation . Phosphorylates SRPK2 and enhances itskinase activity towards SRSF2 and ACIN1 and promotes its nucleartranslocation . Phosphorylates RAF1 at 'Ser-259' andnegatively regulates its activity . Phosphorylation ofBAD stimulates its pro-apoptotic activity .Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits theinteraction of KAT6A with PML and negatively regulates its acetylationactivity towards p53/TP53 . Phosphorylates palladin, modulating cytoskeletal organization and cell motility. Phosphorylates prohibitin , playing animportant role in cell metabolism and proliferation .Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' inducesits release from CDK2 and cytoplasmic relocalization .These recent findings indicate that the AKT1 isoform has a morespecific role in cell motility and proliferation .Phosphorylates CLK2 thereby controlling cell survival to ionizingradiation . Phosphorylates PCK1 at 'Ser-90', reducingthe binding affinity of PCK1 to oxaloacetate and changing PCK1 into anatypical protein kinase activity using GTP as donor .Also acts as an activator of TMEM175 potassium channel activity inresponse to growth factors: forms the lysoK complex together withTMEM175 and acts by promoting TMEM175 channel activation, independentlyof its protein kinase activity . Acts as a regulatorof mitochondrial calcium uptake by mediating phosphorylation of MICU1in the mitochondrial intermembrane space, impairing MICU1 maturation. Acts as an inhibitor of tRNA methylation bymediating phosphorylation of the N-terminus of METTL1, therebyinhibiting METTL1 methyltransferase activity . Inresponse to LPAR1 receptor pathway activation, phosphorylatesRabin8/RAB3IP which alters its activity and phosphorylates WDR44 whichinduces WDR44 binding to Rab11, thereby switching Rab11 vesicularfunction from preciliary trafficking to endocytic recycling. {ECO:0000250|UniProtKB:P31750,ECO:0000250|UniProtKB:P47196, ECO:0000269|PubMed:10358075,ECO:0000269|PubMed:10576742, ECO:0000269|PubMed:10926925,ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11994271,ECO:0000269|PubMed:12150915, ECO:0000269|PubMed:12172553,ECO:0000269|PubMed:12176338, ECO:0000269|PubMed:12964941,ECO:0000269|PubMed:15861136, ECO:0000269|PubMed:16139227,ECO:0000269|PubMed:16982699, ECO:0000269|PubMed:17726016,ECO:0000269|PubMed:18507042, ECO:0000269|PubMed:19592491,ECO:0000269|PubMed:19934221, ECO:0000269|PubMed:20086174,ECO:0000269|PubMed:20471940, ECO:0000269|PubMed:20682768,ECO:0000269|PubMed:23431171, ECO:0000269|PubMed:30504268,ECO:0000269|PubMed:31204173, ECO:0000269|PubMed:31548394,ECO:0000269|PubMed:32228865, ECO:0000269|PubMed:32322062,ECO:0000269|PubMed:33594058, ECO:0000269|PubMed:9829964,ECO:0000303|PubMed:11882383, ECO:0000303|PubMed:15526160,ECO:0000303|PubMed:21432781, ECO:0000303|PubMed:21620960}.
• Uniprot ID: AKT1_HUMAN
• Ensembl ID: ENSG0000014220819
• HGNC ID: HGNC:391

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

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Alpelisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Head and neck cancer [ICD-11: 2D42.0] [1]

• Sensitive Disease: Head and neck cancer [ICD-11: 2D42.0]
• Sensitive Drug: Alpelisib
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: Cal-33 cells; Tongue; Homo sapiens (Human); CVCL_1108
• In Vitro Model: FaDu cells; Pharynx; Homo sapiens (Human); CVCL_1218
• In Vitro Model: HSC-4 cells; Cervical lymph node; Homo sapiens (Human); CVCL_1289
• In Vitro Model: SAS cells; Oral; Homo sapiens (Human); CVCL_1675
• In Vitro Model: UT-SCC-5 cells; Head and Neck; Homo sapiens (Human); CVCL_7858
• In Vitro Model: UT-SCC-8 cells; Head and Neck; Homo sapiens (Human); CVCL_7869
• In Vitro Model: UT-SCC-14 cells; Head and Neck; Homo sapiens (Human); CVCL_7810
• In Vitro Model: UT-SCC-15 cells; Head and Neck; Homo sapiens (Human); CVCL_7811
• Experiment for Molecule Alteration: Whole exome sequencing assay; Western blot assay; Akt activity assay; 3D foci assay; Phosphorylation pathway analysis; Gene enrichment assay; Network analysis; Functional enrichment analysis
• Experiment for Drug Resistance: 3D colony formation assay
• Mechanism Description: In terms of PI3K/Akt pathway activity, Alpelisib treatment reduced phosphorylation of Akt (Ser473), GSK3beta (Ser9) and 4E-BP1 (Ser65) to a similar extent in responder and non-responder cell models (Fig. 2A, B and S2). Likewise, Akt activity was not significantly modified upon Alpelisib exposure (Fig. 2C). Taken together, our data show that inhibition of PI3Kalpha kinase causes varying degrees of radiochemosensitization in different HNSCC models and without an obvious mutational biomarker to predict drug effect.

References

• Ref 1: beta1 integrin mediates unresponsiveness to PI3Kalpha inhibition for radiochemosensitization of 3D HNSCC models. Biomed Pharmacother. 2024 Feb;171:116217.