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AXIN1

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(Redirected from Axin)

"Axin" redirects here. For the unincorporated community in Michigan, see Axin, Michigan.
AXIN1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesAXIN1, AXIN, PPP1R49, axin 1
External IDsOMIM: 603816; MGI: 1096327; HomoloGene: 2614; GeneCards: AXIN1; OMA:AXIN1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8312

12005

Ensembl

ENSG00000103126

ENSMUSG00000024182

UniProt

O15169

O35625

RefSeq (mRNA)

NM_003502
NM_181050

NM_001159598
NM_009733
NM_001394381
NM_001394382
NM_001394389

RefSeq (protein)

NP_003493
NP_851393

NP_001153070
NP_033863
NP_001381310
NP_001381311
NP_001381318

Location (UCSC)Chr 16: 0.29 – 0.35 MbChr 17: 26.36 – 26.41 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Axin-1 is a protein that in humans is encoded by the AXIN1 gene.[5]

Function

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This gene encodes a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded protein interacts with adenomatosis polyposis coli, catenin (cadherin-associated protein) beta 1, glycogen synthase kinase 3 beta, protein phosphatase 2, and itself. This protein functions as a negative regulator of the wingless-type MMTV integration site family, member 1 (WNT) signaling pathway and can induce apoptosis. The crystal structure of a portion of this protein, alone and in a complex with other proteins, has been resolved. Mutations in this gene have been associated with hepatocellular carcinoma, hepatoblastomas, ovarian endometrioid adenocarcinomas, and medulloblastomas. Two transcript variants encoding distinct isoforms have been identified for this gene.[6]

The AXIN proteins attract substantial interest in cancer research as AXIN1 and AXIN2 work synergistically to control pro-oncogenic β-catenin signaling. Importantly, activity in the β-catenin destruction complex can be increased by tankyrase inhibitors and are a potential therapeutic option to reduce the growth of β-catenin-dependent cancers.[7] Mutation in AXIN1 can provoke cancerous disease. AXIN1-truncating mutations at least partially affect β-catenin regulation, whereas this is only the case for a subset of missense mutations. Consistently, most colorectal and liver cancers carrying missense variants acquire mutations in other β-catenin regulatory genes such as APC and CTNNB1.[8] Thus AXIN1 has emerged as an important oncogen in various gastrointestinal and liver cancers.

Structure

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The full-length human protein comprises 862 amino acids with a (predicted) molecular mass of 96 kDa. The N-terminal RGS domain, a GSK3 kinase interacting peptide of Axin1 and homologs of the C-terminal DIX domains have been solved at atomic resolution. Large WNT-downregulating central regions have been characterized as intrinsically disordered by biophysical experiments and bioinformatic analysis.[9] Biophysical destabilization of the folded RGS domain induces formation of nanoaggregates that expose and locally concentrate intrinsically disordered regions, which in turn misregulate Wnt signalling. Many other large IDPs (Intrinsically Disordered Proteins) are affected by missense mutations, such as BRCA1, Adenomatous polyposis coli, CREB-binding protein/(CBP) and might be affected in similar ways by missense mutations of their folded domains.[10]

Interactions

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AXIN1 has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000103126 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024182 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL, et al. (August 1997). "The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation". Cell. 90 (1): 181–92. doi:10.1016/S0092-8674(00)80324-4. PMID 9230313. S2CID 10565695.
  6. ^ "Entrez Gene: AXIN1 axin 1".
  7. ^ Wang W, Liu P, Lavrijsen M, Li S, Zhang R, Li S, et al. (April 2021). "Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines". Scientific Reports. 11 (1): 7470. Bibcode:2021NatSR..11.7470W. doi:10.1038/s41598-021-87091-4. PMC 8018973. PMID 33811251.
  8. ^ Zhang R, Li S, Schippers K, Li Y, Eimers B, Lavrijsen M, et al. (May 2024). "Analysis of Tumor-Associated AXIN1 Missense Mutations Identifies Variants That Activate β-Catenin Signaling". Cancer Research. 84 (9): 1443–1459. doi:10.1158/0008-5472.CAN-23-2268. PMC 11063763. PMID 38359148.
  9. ^ Noutsou M, Duarte AM, Anvarian Z, Didenko T, Minde DP, Kuper I, et al. (2011). "Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded". J Mol Biol. 405 (3): 773–86. doi:10.1016/j.jmb.2010.11.013. PMID 21087614.
  10. ^ Anvarian Z, Nojima H, van Kappel EC, Madl T, Spit M, Viertler M, et al. (2016). "Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network". Nat Struct Mol Biol. 23 (4): 324–32. doi:10.1038/nsmb.3191. hdl:1874/344404. PMID 26974125. S2CID 30761541.[permanent dead link]
  11. ^ a b c Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, et al. (June 1998). "Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level". Genes Cells. 3 (6): 395–403. doi:10.1046/j.1365-2443.1998.00198.x. PMID 9734785. S2CID 10875463.
  12. ^ Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH (June 2003). "Regulation of the Wnt signaling pathway by disabled-2 (Dab2)". EMBO J. 22 (12): 3084–94. doi:10.1093/emboj/cdg286. PMC 162138. PMID 12805222.
  13. ^ a b c Zhang Y, Qiu WJ, Chan SC, Han J, He X, Lin SC (May 2002). "Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways". J. Biol. Chem. 277 (20): 17706–12. doi:10.1074/jbc.M111982200. PMID 11884395.
  14. ^ a b Kim MJ, Chia IV, Costantini F (November 2008). "SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability". FASEB J. 22 (11): 3785–94. doi:10.1096/fj.08-113910. PMC 2574027. PMID 18632848.
  15. ^ Li L, Yuan H, Weaver CD, Mao J, Farr GH, Sussman DJ, et al. (August 1999). "Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1". EMBO J. 18 (15): 4233–40. doi:10.1093/emboj/18.15.4233. PMC 1171499. PMID 10428961.
  16. ^ a b Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS (February 2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity". J. Biol. Chem. 278 (8): 5947–51. doi:10.1074/jbc.C200473200. PMID 12511557.
  17. ^ Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, et al. (April 2001). "Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway". Mol. Cell. 7 (4): 801–9. doi:10.1016/S1097-2765(01)00224-6. PMID 11336703.
  18. ^ Zhang Y, Neo SY, Han J, Lin SC (August 2000). "Dimerization choices control the ability of axin and dishevelled to activate c-Jun N-terminal kinase/stress-activated protein kinase". J. Biol. Chem. 275 (32): 25008–14. doi:10.1074/jbc.M002491200. PMID 10829020.
  19. ^ Yamamoto H, Hinoi T, Michiue T, Fukui A, Usui H, Janssens V, et al. (July 2001). "Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A". J. Biol. Chem. 276 (29): 26875–82. doi:10.1074/jbc.M100443200. PMID 11297546.
  20. ^ Spit M, Fenderico N, Jordens I, Radaszkiewicz T, Lindeboom RG, Bugter JM, et al. (September 2020). "RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer". The EMBO Journal. 39 (18): e103932. doi:10.15252/embj.2019103932. PMC 7503102. PMID 32965059.

Further reading

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