Molecule Information

General Information of the Molecule (ID: Mol04363)

• Name: Catenin beta-1 (CTNNB1) ,Homo sapiens
• Synonyms: Beta-catenin
• Molecule Type: Protein
• Gene Name: CTNNB1
• Gene ID: 1499
• Sequence:
  MATQADLMELDMAMEPDRKAAVSHWQQQSYLDSGIHSGATTTAPSLSGKGNPEEEDVDTS
  QVLYEWEQGFSQSFTQEQVADIDGQYAMTRAQRVRAAMFPETLDEGMQIPSTQFDAAHP
  T NVQRLAEPSQMLKHAVVNLINYQDDAELATRAIPELTKLLNDEDQVVVNKAAVMVHQL
  SK KEASRHAIMRSPQMVSAIVRTMQNTNDVETARCTAGTLHNLSHHREGLLAIFKSGGI
  PAL VKMLGSPVDSVLFYAITTLHNLLLHQEGAKMAVRLAGGLQKMVALLNKTNVKFLAI
  TTDC LQILAYGNQESKLIILASGGPQALVNIMRTYTYEKLLWTTSRVLKVLSVCSSNKP
  AIVEA GGMQALGLHLTDPSQRLVQNCLWTLRNLSDAATKQEGMEGLLGTLVQLLGSDDI
  NVVTCA AGILSNLTCNNYKNKMMVCQVGGIEALVRTVLRAGDREDITEPAICALRHLTS
  RHQEAEM AQNAVRLHYGLPVVVKLLHPPSHWPLIKATVGLIRNLALCPANHAPLREQGA
  IPRLVQLL VRAHQDTQRRTSMGGTQQQFVEGVRMEEIVEGCTGALHILARDVHNRIVIR
  GLNTIPLFV QLLYSPIENIQRVAAGVLCELAQDKEAAEAIEAEGATAPLTELLHSRNEG
  VATYAAAVLF RMSEDKPQDYKKRLSVELTSSLFRTEPMAWNETADLGLDIGAQGEPLGY
  RQDDPSYRSFH SGGYGQDALGMDPMMEHEMGGHHPGADYPVDGLPDLGHAQDLMDGLPP
  GDSNQLAWFDTD L
• Function: Key downstream component of the canonical Wnt signalingpathway . In the absence of Wnt, forms a complex with AXIN1,AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC andits subsequent degradation by the proteasome . In the presence ofWnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus,where it acts as a coactivator for transcription factors of the TCF/LEFfamily, leading to activate Wnt responsive genes . Also acts as acoactivator for other transcription factors, such as NR5A2. Promotes epithelial to mesenchymaltransition/mesenchymal to epithelial transition via drivingtranscription of CTNNB1/TCF-target genes . Involved inthe regulation of cell adhesion, as component of an E-cadherin:cateninadhesion complex . Acts as a negative regulator ofcentrosome cohesion . Involved in theCDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinalepithelial cells and promotes their anchorage-independent growth bydown-regulating DAPK2 . Disrupts PML function and PML-NB formation by inhibiting RANBP2-mediated sumoylation of PML. Promotes neurogenesis by maintaining sympatheticneuroblasts within the cell cycle . Involved inchondrocyte differentiation via interaction with SOX9: SOX9-bindingcompetes with the binding sites of TCF/LEF within CTNNB1, therebyinhibiting the Wnt signaling . Acts as a positiveregulator of odontoblast differentiation during mesenchymal tooth germformation, via promoting the transcription of differentiation factorssuch as LEF1, BMP2 and BMP4 . Activity is repressed in aMSX1-mediated manner at the bell stage of mesenchymal tooth germformation which prevents premature differentiation of odontoblasts . {ECO:0000250|UniProtKB:Q02248,ECO:0000269|PubMed:17524503, ECO:0000269|PubMed:18077326,ECO:0000269|PubMed:18086858, ECO:0000269|PubMed:18957423,ECO:0000269|PubMed:21262353, ECO:0000269|PubMed:22155184,ECO:0000269|PubMed:22187462, ECO:0000269|PubMed:22647378,ECO:0000269|PubMed:22699938, ECO:0000269|PubMed:29910125}.
• Uniprot ID: CTNB1_HUMAN
• Ensembl ID: ENSG0000016803619
• HGNC ID: HGNC:2514

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) 2 drug(s) in total

Methotrexate

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioma [ICD-11: 2A00.1] [1]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Sensitive Drug: Methotrexate
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta-catenin/MGMT signaling pathway; Regulation; N.A.
• In Vitro Model: U251R cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/beta-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated beta-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/beta-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and beta-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level.

Temozolomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioma [ICD-11: 2A00.1] [1]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Resistant Drug: Temozolomide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta-catenin/MGMT signaling pathway; Regulation; N.A.
• In Vitro Model: U251R cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/beta-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated beta-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/beta-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and beta-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level.

Clinical Trial Drug(s) 1 drug(s) in total

Quizartinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: Quizartinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SPHK1/S1P signaling pathway; Regulation; N.A.
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vivo Model: AML mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Lipidomics profiling assay; RNA sequencing assay; qRT-PCR; ELISA assay
• Experiment for Drug Resistance: Western blot assay; Immunofluorescence assay
• Mechanism Description: We demonstrate that long-term sorafenib or quizartinib treatment upregulates SPHK1/sphingosine-1-phosphate (S1P) signaling, which in turn positively modulates beta-catenin signaling to counteract TKI-mediated suppression of FLT3-mutated AML cells via the S1P2 receptor. Genetic or pharmacological inhibition of SPHK1 potently enhanced the TKI-mediated inhibition of proliferation and apoptosis induction in FLT3-mutated AML cells in vitro. SPHK1 knockdown enhanced sorafenib efficacy and improved survival of AML-xenografted mice. Mechanistically, targeting the SPHK1/S1P/S1P2 signaling synergizes with FLT3 TKIs to inhibit beta-catenin activity by activating the protein phosphatase 2 A (PP2A)-glycogen synthase kinase 3beta (GSK3beta) pathway.

References

• Ref 1: High expression of LncRNA HOTAIR is a risk factor for temozolomide resistance in glioblastoma via activation of the miR-214/beta-catenin/MGMT pathway. Sci Rep. 2024 Oct 31;14(1):26224.
• Ref 2: Concomitant targeting of FLT3 and SPHK1 exerts synergistic cytotoxicity in FLT3-ITD(+) acute myeloid leukemia by inhibiting beta-catenin activity via the PP2A-GSK3beta axis. Cell Commun Signal. 2024 Aug 7;22(1):391.