AXIN1

Last updated
AXIN1
Protein AXIN1 PDB 1dk8.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases AXIN1 , AXIN, PPP1R49, axin 1
External IDs OMIM: 603816 MGI: 1096327 HomoloGene: 2614 GeneCards: AXIN1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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 Mb Chr 17: 26.36 – 26.41 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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

Function

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

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

AXIN1 has been shown to interact with:

Related Research Articles

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">Adenomatous polyposis coli</span> Protein-coding gene in the species Homo sapiens

Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer and desmoid tumors.

<span class="mw-page-title-main">Catenin beta-1</span> Mammalian protein found in humans

Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.

<span class="mw-page-title-main">CTNNBIP1</span> Protein-coding gene in the species Homo sapiens

Beta-catenin-interacting protein 1 is a protein that is encoded in humans by the CTNNBIP1 gene.

<span class="mw-page-title-main">Presenilin-1</span> Protein-coding gene in the species Homo sapiens

Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.

<span class="mw-page-title-main">Glycogen synthase kinase-3 beta</span> Protein-coding gene in the species Homo sapiens

Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the GSK3B gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased susceptibility towards bipolar disorder.

<span class="mw-page-title-main">PPP1CA</span> Enzyme

Serine/threonine-protein phosphatase PP1-alpha catalytic subunit is an enzyme that in humans is encoded by the PPP1CA gene.

<span class="mw-page-title-main">IQGAP1</span>

Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene. IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of the actin cytoskeleton, transcription, and cellular adhesion to regulating the cell cycle.

<span class="mw-page-title-main">DVL1</span> Human protein and coding gene

Segment polarity protein dishevelled homolog DVL-1 is a protein that in humans is encoded by the DVL1 gene.

<span class="mw-page-title-main">SGK3</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase Sgk3 is an enzyme that in humans is encoded by the SGK3 gene.

<span class="mw-page-title-main">LRP6</span> Protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

<span class="mw-page-title-main">TAB1</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 is an enzyme that in humans is encoded by the TAB1 gene.

<span class="mw-page-title-main">AXIN2</span> Protein-coding gene in the species Homo sapiens

Axin-2, also known as axin-like protein (Axil), axis inhibition protein 2 (AXIN2), or conductin, is a protein that in humans is encoded by the AXIN2 gene.

<span class="mw-page-title-main">WNT7A</span> Protein-coding gene in the species Homo sapiens

Protein Wnt-7a is a protein that in humans is encoded by the WNT7A gene.

<span class="mw-page-title-main">DVL2</span> Human protein and coding gene

Segment polarity protein dishevelled homolog DVL-2 is a protein that in humans is encoded by the DVL2 gene.

<span class="mw-page-title-main">DYRK1B</span> Protein-coding gene in the species Homo sapiens

Dual specificity tyrosine-phosphorylation-regulated kinase 1B is an enzyme that in humans is encoded by the DYRK1B gene.

<span class="mw-page-title-main">FRAT1</span> Protein-coding gene in the species Homo sapiens

Proto-oncogene FRAT1 is a protein that in humans is encoded by the FRAT1 gene.

<span class="mw-page-title-main">AKAP11</span> Human protein-coding gene

A-kinase anchor protein 11 is an enzyme that in humans is encoded by the AKAP11 gene.

<span class="mw-page-title-main">DVL3</span> Protein-coding gene in the species Homo sapiens

Segment polarity protein dishevelled homolog DVL-3 is a protein that in humans is encoded by the DVL3 gene.

<span class="mw-page-title-main">FRAT2</span> Protein-coding gene in the species Homo sapiens

GSK-3-binding protein FRAT2 is a protein that in humans is encoded by the FRAT2 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000103126 Ensembl, May 2017
  2. 1 2 3 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, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F (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, van de Geer WS, van de Werken HJ, Peppelenbosch MP, Smits R (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, Wang L, Cui G, Chen X, Peppelenbosch MP, Lebbink JH, Smits R (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 . PMID   38359148.
  9. Noutsou M, Duarte AM, Anvarian Z, Didenko T, Minde DP, Kuper I, de Ridder I, Oikonomou C, Friedler A, Boelens R, Rüdiger SG, Maurice MM (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, Jordens I, Low TY, van Scherpenzeel RC, Kuper I, Richter K, Heck AJ, Boelens R, Vincent JP, Rüdiger SG, Maurice MM (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. 1 2 3 Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T (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. 1 2 3 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. 1 2 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, Jonkers J, Kimelman D, Wu D (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. 1 2 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, Yuan H, Takada S, Kimelman D, Li L, Wu D (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, Van Hoof C, Goris J, Asashima M, Kikuchi A (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, Cristobal A, Ootes L, van Osch M, Janssen E, Boonekamp KE, Hanakova K, Potesil D, Zdrahal Z, Boj SF, Medema JP, Bryja V, Koo BK, Vermeulen M, Maurice MM (15 September 2020). "RNF 43 truncations trap CK 1 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