Molecule Information

General Information of the Molecule (ID: Mol04042)

• Name: Ribosomal protein S6 kinase (S6K) ,Homo sapiens
• Synonyms: 90 kDa ribosomal protein S6 kinase 3; Insulin-stimulated protein kinase 1; MAP kinase-activated protein kinase 1b; Ribosomal S6 kinase 2; pp90RSK2
• Molecule Type: Protein
• Gene Name: RPS6KA3
• Gene ID: 6197
• Location: chrX:20149911-20267519[-]
• Sequence:
  MPLAQLADPWQKMAVESPSDSAENGQQIMDEPMGEEEINPQTEEVSIKEIAITHHVKEGH
  EKADPSQFELLKVLGQGSFGKVFLVKKISGSDARQLYAMKVLKKATLKVRDRVRTKMERD
  ILVEVNHPFIVKLHYAFQTEGKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALA
  LDHLHSLGIIYRDLKPENILLDEEGHIKLTDFGLSKESIDHEKKAYSFCGTVEYMAPEVV
  NRRGHTQSADWWSFGVLMFEMLTGTLPFQGKDRKETMTMILKAKLGMPQFLSPEAQSLLR
  MLFKRNPANRLGAGPDGVEEIKRHSFFSTIDWNKLYRREIHPPFKPATGRPEDTFYFDPE
  FTAKTPKDSPGIPPSANAHQLFRGFSFVAITSDDESQAMQTVGVHSIVQQLHRNSIQFTD
  GYEVKEDIGVGSYSVCKRCIHKATNMEFAVKIIDKSKRDPTEEIEILLRYGQHPNIITLK
  DVYDDGKYVYVVTELMKGGELLDKILRQKFFSEREASAVLFTITKTVEYLHAQGVVHRDL
  KPSNILYVDESGNPESIRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDAACD
  IWSLGVLLYTMLTGYTPFANGPDDTPEEILARIGSGKFSLSGGYWNSVSDTAKDLVSKML
  HVDPHQRLTAALVLRHPWIVHWDQLPQYQLNRQDAPHLVKGAMAATYSALNRNQSPVLEP
  VGRSTLAQRRGIKKITSTAL
• 3D-structure: PDB ID: 4JG6; Classification: Transferase/transferase inhibitor; Method: X-ray diffraction; Resolution: 2.60 Å
• Function: Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro- apoptotic function of BAD and DAPK1 (PubMed:16213824, PubMed:16223362, PubMed:17360704, PubMed:9770464). In fibroblast, is required for EGF- stimulated phosphorylation of CREB1 and histone H3 at 'Ser-10', which results in the subsequent transcriptional activation of several immediate-early genes (PubMed:10436156, PubMed:9770464). In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP (PubMed:16223362). Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity (PubMed:8250835). Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex (PubMed:17360704). In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation (PubMed:18508509, PubMed:18813292). Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin- sensitive signaling independently of the PI3K/AKT pathway (PubMed:18722121). Mediates cell survival by phosphorylating the pro- apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function (PubMed:16213824). Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4) (PubMed:18508509, PubMed:18813292). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression (By similarity). In LPS-stimulated dendritic cells, is involved in TLR4- induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3 (By similarity). Negatively regulates EGF-induced MAPK1/3 phosphorylation via phosphorylation of SOS1 (By similarity). Phosphorylates SOS1 at 'Ser-1134' and 'Ser-1161' that create YWHAB and YWHAE binding sites and which contribute to the negative regulation of MAPK1/3 phosphorylation (By similarity). Phosphorylates EPHA2 at 'Ser- 897', the RPS6KA-EPHA2 signaling pathway controls cell migration (PubMed:26158630). Acts as a regulator of osteoblast differentiation by mediating phosphorylation of ATF4, thereby promoting ATF4 transactivation activity (By similarity). .
• Uniprot ID: KS6A3_HUMAN
• Ensembl ID: ENSG00000177189
• HGNC ID: HGNC:10432

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

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

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

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [1]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3-TR cells; Ovary; Homo sapiens (Human); CVCL_HF69
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.

References

• Ref 1: Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway. Int J Mol Sci. 2022 Aug 6;23(15):8761.