AXIN1
AXIN1Axin-1은 인간에게 AXIN1 유전자에 의해 암호화된 단백질이다.[5]
함수
이 유전자는 지단백질신호(RGS) 영역과 흐트러진 액신(DIX) 영역의 조절을 포함하는 세포질 단백질을 암호화한다.인코딩된 단백질은 아데노마토증 다종증 대장균, 카테닌(카데린 관련 단백질) 베타 1, 글리코겐 신타아제 키나제 3 베타, 단백질 인산아제 2 및 그 자체와 상호작용을 한다.이 단백질은 날개 없는 MMTV 통합 사이트 패밀리, 멤버 1(WNT) 신호 경로의 음성 조절기로 기능하며 사멸을 유도할 수 있다.이 단백질의 일부분의 결정구조는, 단독으로, 그리고 다른 단백질과 함께 복합적으로, 해결되었다.이 유전자의 돌연변이는 간세포암, 간세포종, 난소내막내막염 아데노카르시노마, 그리고 난소내막염과 연관되어 있다.이 유전자에 대해 구별되는 ISO 양식을 인코딩하는 두 가지 대본 변형이 확인되었다.[6]
AXIN 단백질은 AXIN1과 AX로서 암 연구에 상당한 관심을 가지고 있다.IN2는 시너지 작용으로 프로-온증 유발 β-카테닌 신호를 제어한다.중요한 것은 β-catenin 파괴 복합체에서의 활동은 tankyrase 억제제에 의해 증가할 수 있으며 β-catenin 의존성 암의 성장을 감소시킬 수 있는 잠재적 치료 옵션이다.[7]
구조
전장 인간 단백질은 96 kDa의 분자 질량을 가진 862개의 아미노산으로 구성되어 있다.Axin1의 GSK3 키나아제 상호작용 펩타이드와 C-단자 DIX 도메인의 호몰로고인 N-단자 RGS 도메인이 원자 분해능으로 해결되었다.대규모 WNT 하향 조정 중심 지역은 생물물리학적 실험과 생물정보학적 분석에 의해 본질적으로 질서 정연하게 구분되는 특징이 있다.[8]접힌 RGS 영역의 생물물리학적 불안정성은 본질적으로 질서 없는 영역을 노출하고 국소적으로 집중하는 나노그래그의 형성을 유도하고, 이는 결국 Wnt 신호 전달을 잘못 규정한다.다른 많은 큰 IDP(내성적으로 흐트러진 단백질)는 BRCA1, 아데노마티스성대장균, CREB 결합 단백질/(CBP)과 같은 오감 돌연변이에 의해 영향을 받고 접힌 도메인의 오감 변이에 의해 비슷한 방식으로 영향을 받을 수 있다.[9]
상호작용
AXIN1은 다음과 상호 작용하는 것으로 나타났다.
참조
- ^ a b c GRCh38: 앙상블 릴리스 89: ENSG00000103126 - 앙상블, 2017년 5월
- ^ a b c GRCm38: 앙상블 릴리스 89: ENSMUSG000024182 - 앙상블, 2017년 5월
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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.
- ^ "Entrez Gene: AXIN1 axin 1".
- ^ 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: 7470. doi:10.1038/s41598-021-87091-4. PMC 8018973. PMID 33811251.
- ^ 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.
- ^ 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. PMID 26974125. S2CID 30761541.
- ^ a b c 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Spit, Maureen; Fenderico, Nicola; Jordens, Ingrid; Radaszkiewicz, Tomasz; Lindeboom, Rik GH; Bugter, Jeroen M; Cristobal, Alba; Ootes, Lars; van Osch, Max; Janssen, Eline; Boonekamp, Kim E; Hanakova, Katerina; Potesil, David; Zdrahal, Zbynek; Boj, Sylvia F; Medema, Jan Paul; Bryja, Vitezslav; Koo, Bon‐Kyoung; Vermeulen, Michiel; Maurice, Madelon M (15 September 2020). "RNF 43 truncations trap CK 1 to drive niche‐independent self‐renewal in cancer". The EMBO Journal. 39 (18). doi:10.15252/embj.2019103932. PMID 32965059.
추가 읽기
- Segditsas S, Tomlinson I (2007). "Colorectal cancer and genetic alterations in the Wnt pathway". Oncogene. 25 (57): 7531–7. doi:10.1038/sj.onc.1210059. PMID 17143297.
- Flint J, Thomas K, Micklem G, Raynham H, Clark K, Doggett NA, King A, Higgs DR (1997). "The relationship between chromosome structure and function at a human telomeric region". Nat. Genet. 15 (3): 252–7. doi:10.1038/ng0397-252. PMID 9054936. S2CID 20630444.
- Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A (1998). "Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin". EMBO J. 17 (5): 1371–84. doi:10.1093/emboj/17.5.1371. PMC 1170485. PMID 9482734.
- Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P (1998). "Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta". Curr. Biol. 8 (10): 573–81. doi:10.1016/S0960-9822(98)70226-X. PMID 9601641. S2CID 2863360.
- Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T (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.
- Hsu W, Zeng L, Costantini F (1999). "Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain". J. Biol. Chem. 274 (6): 3439–45. doi:10.1074/jbc.274.6.3439. PMID 9920888.
- Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, Nakamichi I, Kikuchi A, Nakayama K, Nakayama K (1999). "An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin". EMBO J. 18 (9): 2401–10. doi:10.1093/emboj/18.9.2401. PMC 1171323. PMID 10228155.
- Fagotto F, Jho Eh, Zeng L, Kurth T, Joos T, Kaufmann C, Costantini F (1999). "Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization". J. Cell Biol. 145 (4): 741–56. doi:10.1083/jcb.145.4.741. PMC 2133179. PMID 10330403.
- Kodama S, Ikeda S, Asahara T, Kishida M, Kikuchi A (1999). "Axin directly interacts with plakoglobin and regulates its stability". J. Biol. Chem. 274 (39): 27682–8. doi:10.1074/jbc.274.39.27682. PMID 10488109.
- Jho Eh, Lomvardas S, Costantini F (2000). "A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression". Biochem. Biophys. Res. Commun. 266 (1): 28–35. doi:10.1006/bbrc.1999.1760. PMID 10581160.
- Ikeda S, Kishida M, Matsuura Y, Usui H, Kikuchi A (2000). "GSK-3beta-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by beta-catenin and protein phosphatase 2A complexed with Axin". Oncogene. 19 (4): 537–45. doi:10.1038/sj.onc.1203359. PMID 10698523.
- Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y (2000). "AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1". Nat. Genet. 24 (3): 245–50. doi:10.1038/73448. PMID 10700176. S2CID 27531668.
- Spink KE, Polakis P, Weis WI (2000). "Structural basis of the Axin-adenomatous polyposis coli interaction". EMBO J. 19 (10): 2270–9. doi:10.1093/emboj/19.10.2270. PMC 384355. PMID 10811618.
- Zhang Y, Neo SY, Han J, Lin SC (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.
- Daniels RJ, Peden JF, Lloyd C, Horsley SW, Clark K, Tufarelli C, Kearney L, Buckle VJ, Doggett NA, Flint J, Higgs DR (2001). "Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16". Hum. Mol. Genet. 10 (4): 339–52. doi:10.1093/hmg/10.4.339. PMID 11157797.
- Yamamoto H, Hinoi T, Michiue T, Fukui A, Usui H, Janssens V, Van Hoof C, Goris J, Asashima M, Kikuchi A (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.
- Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D (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.
- Furuhashi M, Yagi K, Yamamoto H, Furukawa Y, Shimada S, Nakamura Y, Kikuchi A, Miyazono K, Kato M (2001). "Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway". Mol. Cell. Biol. 21 (15): 5132–41. doi:10.1128/MCB.21.15.5132-5141.2001. PMC 87238. PMID 11438668.
- Rubinfeld B, Tice DA, Polakis P (2001). "Axin-dependent phosphorylation of the adenomatous polyposis coli protein mediated by casein kinase 1epsilon". J. Biol. Chem. 276 (42): 39037–45. doi:10.1074/jbc.M105148200. PMID 11487578.