Polo-like kinases

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Polo-like kinases (German: “Polo-like kinases ”, PLK) are important regulatory enzymes for the cell cycle of eukaryotes and were first described in 1993 in fruit flies . The PLK are involved in the formation and modification of the mitotic spindle and in the activation of the CDK / cyclin complex of the cell cycle.

PLK represent a family of evolutionarily conserved serine / threonine kinases that promote cell cycle progression. They have the enzyme number EC  2.7.11.21 . Most species have only one form of PLK; PLK1 to PLK5 are known in humans.

structure

The polo-like kinases contain a conserved kinase domain at the N-terminus as well as a catalytically inactive polo box domain near the C-terminus , which consists of one or two polo box motifs. Polo box dimers bind the peptide sequence Ser- (pSer- / pTyr) - (P / X), thus enabling protein-protein interactions and thus controlling substrate binding and the location of the kinase within the cell, for example by binding to mitotic cells Structures such as the centrosome and spindle apparatus .

The polo box domain can only be found within the PLK family and is not found in any other protein .

effect

PLK mediate the transition from phase G2 to phase M during the cell cycle, activation of CDC25 and mitotic processes including centrosome maturation, formation of the spindle apparatus, activation of the anaphase-promoting complex (APC), chromosome migration and actin ring formation (cytokinesis). Mammalian PLK1 is involved in the regulation of major steps in cell division, DNA damage repair, apoptosis and the advancement of the cell cycle. The PLK3 is a multifunctional enzyme for the stress response in the cell. It is activated by signals after DNA damage and / or damage to the mitotic spindle. The substrates include Chk2 and p53 .

Medical research

In particular, PLK1 is of great interest for medical research, since overexpression of this kinase can often be observed in tumors and PLK1 contributes to tumor growth due to its proliferative effect. A negative regulation of p53 by PLK1 could also be observed. PLK1 overexpression also overrides various mitotic checkpoints, which compromises genome stability. If PLK1 overexpression is found in a tumor, this means a poorer prognosis for the patient.

The inhibition of PLK1 can take place either by inhibiting the kinase domain or by inhibiting the polo box domain: While the selective inhibition of kinase domains is not trivial due to the great structural similarities of the active centers, the polo box domain, which occurs exclusively in PLK, ceases an attractive alternative target.

The non-peptide , ATP -competitive kinase inhibitor BI2536 is in the clinical phase for approval as a chemotherapeutic agent . Examples of inhibitors of the polo box domain are purpurogallin, thymoquinone and poloxin.

Klaus Strebhardt and colleagues from the University Hospital Frankfurt / M. found in RNAi experiments with oncomice and cell cultures that cancer cells absolutely need PLK to survive, whereas healthy cells do not.

See also

Protein kinase PLK1

literature

  • Strebhardt, Klaus: Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy. In: Nature Reviews Drug Discovery . 8 2010, pp. 643-660.
  • Schöffski, Patrick: Polo-Like Kinase (PLK) Inhibitors in Preclinical and Early Clinical Development in Oncology. In: Oncologist . 2009, pp. 559-570.

Individual evidence

  1. ↑ FJ Clay, SJ McEwen, I Bertoncello, AF Wilks, AR Dunn: Identification and cloning of a protein kinase-encoding mouse gene, Plk, related to the polo gene of Drosophila . In: PNAS 1993 90 (11) 4882-488.
  2. ↑ DM Glover, IM Hagan, AAM Tavares: Polo-like kinases: a team that plays throughout mitosis. In: Genes & Development. 12, 1998, pp. 3777-3787, doi : 10.1101 / gad.12.24.3777 .
  3. ↑ UniProt search result protein family
  4. ^ BC van de Weerdt, RH Medema: Polo-like kinases: a team in control of the division. In: Cell cycle (Georgetown, Tex.). Volume 5, Number 8, April 2006, pp. 853-864, ISSN  1551-4005 . PMID 16627997 . (Review).
  5. ↑ S. Xie: Plk3 Functionally Links DNA Damage to Cell Cycle Arrest and Apoptosis at Least in Part via the p53 Pathway. In: Journal of Biological Chemistry . 276, pp. 43305-43312, doi : 10.1074 / jbc.M106050200 .
  6. ↑ Nature Communications: Toxicity modeling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells
  7. ↑ FAZ of July 20, 2011, p. N1