4yyp

Structural highlights

Disease

[STIL_HUMAN] Precursor T-cell acute lymphoblastic leukemia;Autosomal recessive primary microcephaly. A chromosomal aberration involving STIL may be a cause of some T-cell acute lymphoblastic leukemias (T-ALL). A deletion at 1p32 between STIL and TAL1 genes leads to STIL/TAL1 fusion mRNA with STIL exon 1 slicing to TAL1 exon 3. As both STIL exon 1 and TAL1 exon 3 are 5'-untranslated exons, STIL/TAL1 fusion mRNA predicts a full length TAL1 protein under the control of the STIL promoter, leading to inappropriate TAL1 expression. In childhood T-cell malignancies (T-ALL), a type of defect such as STIL/TAL1 fusion is associated with a good prognosis. In cultured lymphocytes from healthy adults, STIL/TAL1 fusion mRNA may be detected after 7 days of culture. The disease is caused by mutations affecting the gene represented in this entry.

Function

[PLK4_HUMAN] Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2.^{[1] [2] [3] [4] [5] [6]} [STIL_HUMAN] Immediate-early gene. Plays an important role in embryonic development as well as in cellular growth and proliferation; its long-term silencing affects cell survival and cell cycle distribution as well as decreases CDK1 activity correlated with reduced phosphorylation of CDK1. Plays a role as a positive regulator of the sonic hedgehog pathway, acting downstream of PTCH1.^{[7] [8]}

References

1. ↑ Bettencourt-Dias M, Rodrigues-Martins A, Carpenter L, Riparbelli M, Lehmann L, Gatt MK, Carmo N, Balloux F, Callaini G, Glover DM. SAK/PLK4 is required for centriole duplication and flagella development. Curr Biol. 2005 Dec 20;15(24):2199-207. Epub 2005 Dec 1. PMID:16326102 doi:http://dx.doi.org/10.1016/j.cub.2005.11.042
2. ↑ Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA. The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol. 2005 Nov;7(11):1140-6. PMID:16244668 doi:http://dx.doi.org/10.1038/ncb1320
3. ↑ Kleylein-Sohn J, Westendorf J, Le Clech M, Habedanck R, Stierhof YD, Nigg EA. Plk4-induced centriole biogenesis in human cells. Dev Cell. 2007 Aug;13(2):190-202. PMID:17681131 doi:http://dx.doi.org/10.1016/j.devcel.2007.07.002
4. ↑ Bonni S, Ganuelas ML, Petrinac S, Hudson JW. Human Plk4 phosphorylates Cdc25C. Cell Cycle. 2008 Feb 15;7(4):545-7. Epub 2007 Nov 25. PMID:18239451
5. ↑ Petrinac S, Ganuelas ML, Bonni S, Nantais J, Hudson JW. Polo-like kinase 4 phosphorylates Chk2. Cell Cycle. 2009 Jan 15;8(2):327-9. PMID:19164942
6. ↑ Puklowski A, Homsi Y, Keller D, May M, Chauhan S, Kossatz U, Grunwald V, Kubicka S, Pich A, Manns MP, Hoffmann I, Gonczy P, Malek NP. The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication. Nat Cell Biol. 2011 Jul 3;13(8):1004-9. doi: 10.1038/ncb2282. PMID:21725316 doi:http://dx.doi.org/10.1038/ncb2282
7. ↑ Campaner S, Kaldis P, Izraeli S, Kirsch IR. Sil phosphorylation in a Pin1 binding domain affects the duration of the spindle checkpoint. Mol Cell Biol. 2005 Aug;25(15):6660-72. PMID:16024801 doi:http://dx.doi.org/10.1128/MCB.25.15.6660-6672.2005
8. ↑ Izraeli S, Colaizzo-Anas T, Bertness VL, Mani K, Aplan PD, Kirsch IR. Expression of the SIL gene is correlated with growth induction and cellular proliferation. Cell Growth Differ. 1997 Nov;8(11):1171-9. PMID:9372240
9. ↑ Arquint C, Gabryjonczyk AM, Imseng S, Bohm R, Sauer E, Hiller S, Nigg EA, Maier T. STIL binding to Polo-box 3 of PLK4 regulates centriole duplication. Elife. 2015 Jul 18;4. doi: 10.7554/eLife.07888. PMID:26188084 doi:http://dx.doi.org/10.7554/eLife.07888