Molecule Information

General Information of the Molecule (ID: Mol04398)

• Name: 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1) ,Homo sapiens
• Synonyms: Acetyl-CoA carboxylase kinase; Hydroxymethylglutaryl-CoA reductase kinase; Tau-protein kinase PRKAA1
• Molecule Type: Protein
• Gene Name: PRKAA1
• Gene ID: 5562
• Sequence:
  MRRLSSWRKMATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNR
  QKIRSLDVVGKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKN
  G RLDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDG
  EF LRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLFKKI
  CDG IFYTPQYLNPSVISLLKHMLQVDPMKRATIKDIREHEWFKQDLPKYLFPEDPSYSS
  TMID DEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLAT
  SPPDS FLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQ
  SRPNDI MAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLD
  FRSIDDE ITEAKSGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSP
  VDLTPRPG SHTIEFFEMCANLIKILAQ
• Function: Catalytic subunit of AMP-activated protein kinase , anenergy sensor protein kinase that plays a key role in regulatingcellular energy metabolism . In response to reduction ofintracellular ATP levels, AMPK activates energy-producing pathways andinhibits energy-consuming processes: inhibits protein, carbohydrate andlipid biosynthesis, as well as cell growth and proliferation. AMPK acts via directphosphorylation of metabolic enzymes, and by longer-term effects viaphosphorylation of transcription regulators . Regulates lipid synthesis by phosphorylating andinactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCRand LIPE; regulates fatty acid and cholesterol synthesis byphosphorylating acetyl-CoA carboxylase and hormone-sensitive lipase enzymes, respectively . Promoteslipolysis of lipid droplets by mediating phosphorylation of isoform 1of CHKA . Regulates insulin-signaling andglycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 .AMPK stimulates glucose uptake in muscle by increasing thetranslocation of the glucose transporter SLC2A4/GLUT4 to the plasmamembrane, possibly by mediating phosphorylation of TBC1D4/AS160 . Regulates transcription and chromatin structure byphosphorylating transcription regulators involved in energy metabolismsuch as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP,EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A .Acts as a key regulator of glucose homeostasis in liver byphosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration inthe cytoplasm . In response to stress, phosphorylates'Ser-36' of histone H2B , leading to promote transcription. Acts as a key regulator of cell growth andproliferation by phosphorylating FNIP1, TSC2, RPTOR, WDR24 andATG1/ULK1: in response to nutrient limitation, negatively regulates themTORC1 complex by phosphorylating RPTOR component of the mTORC1 complexand by phosphorylating and activating TSC2 . Also phosphorylatesand inhibits GATOR2 subunit WDR24 in response to nutrient limitation,leading to suppress glucose-mediated mTORC1 activation. In response to energetic stress, phosphorylatesFNIP1, inactivating the non-canonical mTORC1 signaling, therebypromoting nuclear translocation of TFEB and TFE3, and inducingtranscription of lysosomal or autophagy genes . Inresponse to nutrient limitation, promotes autophagy by phosphorylatingand activating ATG1/ULK1 . In that process, it alsoactivates WDR45/WIPI4 . Phosphorylates CASP6, therebypreventing its autoprocessing and subsequent activation. In response to nutrient limitation, phosphorylatestranscription factor FOXO3 promoting FOXO3 mitochondrial import . Also acts as a regulator of cellular polarity byremodeling the actin cytoskeleton; probably by indirectly activatingmyosin . AMPK also acts as a regulator of circadianrhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway byphosphorylating CTNNB1, leading to stabilize it . Alsohas tau-protein kinase activity: in response to amyloid beta A4 protein exposure, activated by CAMKK2, leading to phosphorylation ofMAPT/TAU; however the relevance of such data remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 andSLC12A1 . Regulates hepaticlipogenesis. Activated via SIRT3, represses sterol regulatory element-binding protein transcriptional activities and ATP-consuminglipogenesis to restore cellular energy balance. Upon stress, regulatesmitochondrial fragmentation through phosphorylation of MTFR1L. {ECO:0000250|UniProtKB:P54645,ECO:0000250|UniProtKB:Q5EG47, ECO:0000269|PubMed:11518699,ECO:0000269|PubMed:11554766, ECO:0000269|PubMed:12519745,ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15866171,ECO:0000269|PubMed:17486097, ECO:0000269|PubMed:17711846,ECO:0000269|PubMed:18184930, ECO:0000269|PubMed:18439900,ECO:0000269|PubMed:20074060, ECO:0000269|PubMed:20160076,ECO:0000269|PubMed:21205641, ECO:0000269|PubMed:24563466,ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:32029622,ECO:0000269|PubMed:34077757, ECO:0000269|PubMed:36367943,ECO:0000269|PubMed:36732624, ECO:0000269|PubMed:37079666,ECO:0000269|PubMed:37821951, ECO:0000303|PubMed:17307971,ECO:0000303|PubMed:17712357}.
• Uniprot ID: AAPK1_HUMAN
• Ensembl ID: ENSG0000013235612
• HGNC ID: HGNC:9376

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

Cabazitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Prostate cancer [ICD-11: 2C82.0] [1]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cabazitaxel
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxytocin signaling pathway; Activation; hsa04921
• In Vitro Model: DU145CR cells; prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: MS analysis
• Mechanism Description: Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.

References

• Ref 1: G-protein signaling of oxytocin receptor as a potential target for cabazitaxel-resistant prostate cancer. PNAS Nexus. 2024 Jan 4;3(1):pgae002.