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PLK4

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PLK4
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

2N19, 3COK, 4JXF, 4N7V, 4N7Z, 4N9J, 4YUR, 4YYP

Identifikatori
AliasiPLK4
Vanjski ID-jeviOMIM: 605031 MGI: 101783 HomoloGene: 7962 GeneCards: PLK4
Lokacija gena (čovjek)
Hromosom 4 (čovjek)
Hrom.Hromosom 4 (čovjek)[1]
Hromosom 4 (čovjek)
Genomska lokacija za PLK4
Genomska lokacija za PLK4
Bend4q28.1Početak127,880,893 bp[1]
Kraj127,899,224 bp[1]
Lokacija gena (miš)
Hromosom 3 (miš)
Hrom.Hromosom 3 (miš)[2]
Hromosom 3 (miš)
Genomska lokacija za PLK4
Genomska lokacija za PLK4
Bend3|3 BPočetak40,754,454 bp[2]
Kraj40,771,318 bp[2]
Obrazac RNK ekspresije




Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• aktivnost sa transferazom
• nucleotide binding
• protein kinase activity
• kinase activity
• protein serine/threonine kinase activity
• GO:0001948, GO:0016582 vezivanje za proteine
• ATP binding
• vezivanje identičnih proteina
Ćelijska komponenta• citoplazma
• centrosom
• deuterosome
• XY body
• Jedarce
• Centriole
• cleavage furrow
• citoskelet
• jedro
• citosol
Biološki proces• trophoblast giant cell differentiation
• Fosforilacija
• de novo centriole assembly involved in multi-ciliated epithelial cell differentiation
• G2/M transition of mitotic cell cycle
• centriole replication
• positive regulation of centriole replication
• ciliary basal body-plasma membrane docking
• regulation of G2/M transition of mitotic cell cycle
• protein phosphorylation
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

10733

20873

Ensembl

ENSG00000142731

ENSMUSG00000025758

UniProt

O00444

Q64702

RefSeq (mRNK)

NM_001190799
NM_001190801
NM_014264

NM_011495
NM_173169

RefSeq (bjelančevina)

NP_001177728
NP_001177730
NP_055079

NP_035625
NP_775261

Lokacija (UCSC)Chr 4: 127.88 – 127.9 MbChr 3: 40.75 – 40.77 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Serin/treonin-protein kinaza PLK4, znana i kao pololika kinaza 4 jest enzim koji je kod ljudi kodiran genom PLK4 sa hromosoma 4.[5] Homolog Drosophila je SAK, homolog C. elegans je zyg-1, a homolog kod roda Xenopus je Plx4.[6]

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 970 aminokiselina, а molekulska težina 108.972 Da.[7]

1020304050
MATCIGEKIEDFKVGNLLGKGSFAGVYRAESIHTGLEVAIKMIDKKAMYK
AGMVQRVQNEVKIHCQLKHPSILELYNYFEDSNYVYLVLEMCHNGEMNRY
LKNRVKPFSENEARHFMHQIITGMLYLHSHGILHRDLTLSNLLLTRNMNI
KIADFGLATQLKMPHEKHYTLCGTPNYISPEIATRSAHGLESDVWSLGCM
FYTLLIGRPPFDTDTVKNTLNKVVLADYEMPSFLSIEAKDLIHQLLRRNP
ADRLSLSSVLDHPFMSRNSSTKSKDLGTVEDSIDSGHATISTAITASSST
SISGSLFDKRRLLIGQPLPNKMTVFPKNKSSTDFSSSGDGNSFYTQWGNQ
ETSNSGRGRVIQDAEERPHSRYLRRAYSSDRSGTSNSQSQAKTYTMERCH
SAEMLSVSKRSGGGENEERYSPTDNNANIFNFFKEKTSSSSGSFERPDNN
QALSNHLCPGKTPFPFADPTPQTETVQQWFGNLQINAHLRKTTEYDSISP
NRDFQGHPDLQKDTSKNAWTDTKVKKNSDASDNAHSVKQQNTMKYMTALH
SKPEIIQQECVFGSDPLSEQSKTRGMEPPWGYQNRTLRSITSPLVAHRLK
PIRQKTKKAVVSILDSEEVCVELVKEYASQEYVKEVLQISSDGNTITIYY
PNGGRGFPLADRPPSPTDNISRYSFDNLPEKYWRKYQYASRFVQLVRSKS
PKITYFTRYAKCILMENSPGADFEVWFYDGVKIHKTEDFIQVIEKTGKSY
TLKSESEVNSLKEEIKMYMDHANEGHRICLALESIISEEERKTRSAPFFP
IIIGRKPGSTSSPKALSPPPSVDSNYPTRERASFNRMVMHSAASPTQAPI
LNPSMVTNEGLGLTTTASGTDISSNSLKDCLPKSAQLLKSVFVKNVGWAT
QLTSGAVWVQFNDGSQLVVQAGVSSISYTSPNGQTTRYGENEKLPDYIKQ
KLQCLSSILLMFSNPTPNFH

Struktura

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PLK4 sadrži N-terminalni domen kinaze (ostaci 12-284) i C-terminalni lokalizacijski domen (ostaci 596-898).[8] Ostali pololiki članovi kinaza sadrže po dva C-terminalna polo kutijska domena (PBD). PLK4 sadrži ove dva domena uz treći PBD, koji olakšava oligomerizaciju, ciljanje i promovira transautofosforilaciju, ograničavajući duplikaciju centriola, jednom po ćelijskom ciklusu.[8]

Funkcija

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PLK4 kodira člana polo porodice serin/treonin protein kinaza. Protein se nalazi na centriolaama — kompleksnim strukturama zasnovanim na mikrotubula makoje se nalaze u centrosomima — i reguliše duplikaciju centriola tokom ćelijskog ciklusa.[5] Prekomjerna ekspresija PLK4 rezultira amplifikacijom centrosoma, a nokdaun PLK4 rezultira gubitkom centrosoma.[9][10]

Kao meta lijeka protiv raka

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Inhibitori enzimske aktivnosti PLK4 imaju potencijal u liječenju raka.[11][12] PLK4 inhibitor R1530 podregulira ekspresiju kinaze mitozne kontrolne tačke BubR1, što zauzvrat dovodi do poliploidije, čineći ćelije raka nestabilnim i osjetljivijim na emoterapiju. Nasuprot tome, normalne ćelije su otporne na efekte R1530 koji izazivaju poliploidiju.[13]

Drugi inhibitor PLK4, CFI-400945, pokazao je efikasnost na životinjskim modelima raka dojke i jajnika.[14][15]

Za još jedan inhibitor PLK4, centrinon, prijavljeno je da iscrpljuje centriole u ljudskim i drugim tipovima ćelija kičmenjaka, što je rezultiralo zaustavljanjem ćelijskog ciklusa ovisnog o p53 u G1-fazi.[16] Inhibicija PLK4 upotrebom hemijske genetičke strategije potvrdila je ovo p53-zavisno zaustavljanje ćelijskog ciklusa u G1-fazi.[17]

PLK4 je također identificiran kao potencijalna terapijska meta za maligne rabdoidne tumore, meduloblastome i moguće, druge embrionske tumore mozga.[18][19][20][21]

Interakcije i supstrati

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Dokumentirane podloge za PLK4 uključuju STIL, GCP6,[22] Hand1,[23][24] Ect2,[25] FBXW5,[26] i samog sebe (putem autofosforilacije). Autofosforilacija PLK4 rezultira ubikvitinacijom i naknadnim uništavanjem proteasoma.[27][28]

Pokazalo se da PLK4 ulazi u interakcije sa stratifinom.[29]

Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000142731 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025758 - Ensembl, maj 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. ^ a b "Entrez Gene: PLK4 polo-like kinase 4 (Drosophila)".
  6. ^ Shimanovskaya E, Viscardi V, Lesigang J, Lettman MM, Qiao R, Svergun DI, Round A, Oegema K, Dong G (august 2014). "Structure of the C. elegans ZYG-1 cryptic polo box suggests a conserved mechanism for centriolar docking of Plk4 kinases". Structure. 22 (8): 1090–1104. doi:10.1016/j.str.2014.05.009. PMC 4126857. PMID 24980795.
  7. ^ "UniProt, O00444" (jezik: engleski). Pristupljeno 30. 10. 2020.
  8. ^ a b Slevin LK, Nye J, Pinkerton DC, Buster DW, Rogers GC, Slep KC (novembar 2012). "The structure of the plk4 cryptic polo box reveals two tandem polo boxes required for centriole duplication". Structure. 20 (11): 1905–17. doi:10.1016/j.str.2012.08.025. PMC 3496063. PMID 23000383.
  9. ^ Godinho SA, Picone R, Burute M, Dagher R, Su Y, Leung CT, Polyak K, Brugge JS, Théry M, Pellman D (juni 2014). "Oncogene-like induction of cellular invasion from centrosome amplification". Nature. 510 (7503): 167–71. Bibcode:2014Natur.510..167G. doi:10.1038/nature13277. PMC 4061398. PMID 24739973.
  10. ^ Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA (novembar 2005). "The Polo kinase Plk4 functions in centriole duplication". Nature Cell Biology. 7 (11): 1140–6. doi:10.1038/ncb1320. PMID 16244668. S2CID 1349505.
  11. ^ Suri A, Bailey AW, Tavares MT, Gunosewoyo H, Dyer CP, Grupenmacher AT, Piper DR, Horton RA, Tomita T, Kozikowski AP, Roy SM, Sredni ST (april 2019). "Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer". International Journal of Molecular Sciences. 20 (9): 2112. doi:10.3390/ijms20092112. PMC 6540285. PMID 31035676.
  12. ^ Mason J, Wei S, Luo X, Nadeem V, Kiarash R, Huang P, Awrey D, Leung G, Beletskaya I, Feher M, Forrest B, Laufer R, Sampson P, Li SW, Liu Y, Lang Y, Pauls H, Mak T, Pan JG. "Inhibition of Polo-like kinase 4 as an anti-cancer strategy". Abstract LB-215. Cancer Research. str. LB-215. Arhivirano s originala, 24. 6. 2013.
  13. ^ Tovar C, Higgins B, Deo D, Kolinsky K, Liu JJ, Heimbrook DC, Vassilev LT (august 2010). "Small-molecule inducer of cancer cell polyploidy promotes apoptosis or senescence: Implications for therapy". Cell Cycle. 9 (16): 3364–75. doi:10.4161/cc.9.16.12732. PMID 20814247.
  14. ^ "Experimental drug shows promise in treating breast, ovarian cancer". News. Canadian Broadcasting Corporation. 18. 6. 2013.
  15. ^ Yu B, Yu Z, Qi PP, Yu DQ, Liu HM (maj 2015). "Discovery of orally active anticancer candidate CFI-400945 derived from biologically promising spirooxindoles: success and challenges". European Journal of Medicinal Chemistry. 95: 35–40. doi:10.1016/j.ejmech.2015.03.020. PMID 25791677.
  16. ^ Wong YL, Anzola JV, Davis RL, Yoon M, Motamedi A, Kroll A, Seo CP, Hsia JE, Kim SK, Mitchell JW, Mitchell BJ, Desai A, Gahman TC, Shiau AK, Oegema K (juni 2015). "Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4". Science. 348 (6239): 1155–60. doi:10.1126/science.aaa5111. PMC 4764081. PMID 25931445.
  17. ^ Lambrus BG, Uetake Y, Clutario KM, Daggubati V, Snyder M, Sluder G, Holland AJ (juli 2015). "p53 protects against genome instability following centriole duplication failure". The Journal of Cell Biology. 210 (1): 63–77. doi:10.1083/jcb.201502089. PMC 4494000. PMID 26150389.
  18. ^ Sredni ST, Suzuki M, Yang JP, Topczewski J, Bailey AW, Gokirmak T, Gross JN, de Andrade A, Kondo A, Piper DR, Tomita T (novembar 2017). "A functional screening of the kinome identifies the Polo-like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain". Pediatric Blood & Cancer. 64 (11): e26551. doi:10.1002/pbc.26551. PMID 28398638.
  19. ^ Sredni ST, Bailey AW, Suri A, Hashizume R, He X, Louis N, Gokirmak T, Piper DR, Watterson DM, Tomita T (decembar 2017). "Inhibition of polo-like kinase 4 (PLK4): a new therapeutic option for rhabdoid tumors and pediatric medulloblastoma". Oncotarget. 8 (67): 111190–111212. doi:10.18632/oncotarget.22704. PMC 5762315. PMID 29340047.
  20. ^ Bailey AW, Suri A, Chou PM, Pundy T, Gadd S, Raimondi SL, Tomita T, Sredni ST (novembar 2018). "Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB)". Bioengineering. 5 (4): 96. doi:10.3390/bioengineering5040096. PMC 6315664. PMID 30400339.
  21. ^ Suri A, Bailey AW, Tavares MT, Gunosewoyo H, Dyer CP, Grupenmacher AT, Piper DR, Horton RA, Tomita T, Kozikowski AP, Roy SM, Sredni ST (april 2019). "Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer". International Journal of Molecular Sciences. 20 (9): 2112. doi:10.3390/ijms20092112. PMC 6540285. PMID 31035676.
  22. ^ Bahtz R, Seidler J, Arnold M, Haselmann-Weiss U, Antony C, Lehmann WD, Hoffmann I (januar 2012). "GCP6 is a substrate of Plk4 and required for centriole duplication". Journal of Cell Science. 125 (Pt 2): 486–96. doi:10.1242/jcs.093930. PMID 22302995.
  23. ^ Martindill DM, Risebro CA, Smart N, Franco-Viseras Mdel M, Rosario CO, Swallow CJ, Dennis JW, Riley PR (oktobar 2007). "Nucleolar release of Hand1 acts as a molecular switch to determine cell fate". Nature Cell Biology. 9 (10): 1131–41. doi:10.1038/ncb1633. PMID 17891141. S2CID 5110337.
  24. ^ Hudson JW, Kozarova A, Cheung P, Macmillan JC, Swallow CJ, Cross JC, Dennis JW (mart 2001). "Late mitotic failure in mice lacking Sak, a polo-like kinase". Current Biology. 11 (6): 441–6. doi:10.1016/s0960-9822(01)00117-8. PMID 11301255. S2CID 14670796.
  25. ^ Rosario CO, Ko MA, Haffani YZ, Gladdy RA, Paderova J, Pollett A, Squire JA, Dennis JW, Swallow CJ (april 2010). "Plk4 is required for cytokinesis and maintenance of chromosomal stability". Proceedings of the National Academy of Sciences of the United States of America. 107 (15): 6888–93. Bibcode:2010PNAS..107.6888R. doi:10.1073/pnas.0910941107. PMC 2872425. PMID 20348415.
  26. ^ Puklowski A, Homsi Y, Keller D, May M, Chauhan S, Kossatz U, Grünwald V, Kubicka S, Pich A, Manns MP, Hoffmann I, Gönczy P, Malek NP (juli 2011). "The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication". Nature Cell Biology. 13 (8): 1004–9. doi:10.1038/ncb2282. PMID 21725316. S2CID 24052533.
  27. ^ Cunha-Ferreira I, Bento I, Pimenta-Marques A, Jana SC, Lince-Faria M, Duarte P, Borrego-Pinto J, Gilberto S, Amado T, Brito D, Rodrigues-Martins A, Debski J, Dzhindzhev N, Bettencourt-Dias M (novembar 2013). "Regulation of autophosphorylation controls PLK4 self-destruction and centriole number". Current Biology. 23 (22): 2245–54. doi:10.1016/j.cub.2013.09.037. hdl:10400.7/833. PMID 24184099. S2CID 9056074.
  28. ^ Guderian G, Westendorf J, Uldschmid A, Nigg EA (juli 2010). "Plk4 trans-autophosphorylation regulates centriole number by controlling betaTrCP-mediated degradation" (PDF). Journal of Cell Science. 123 (Pt 13): 2163–9. doi:10.1242/jcs.068502. PMID 20516151. S2CID 14815516.
  29. ^ Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (oktobar 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.

Dopunska literatura

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Vanjski linkovi

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