Polo-like kinase

Polo-like kinases (Eng. "Polo -like kinases ", PLK ) are important regulatory enzymes of the cell cycle of eukaryotes and were first described in the fruit fly in 1993. PLK are involved in the formation and change of the mitotic spindle and in the activation of CDK / cyclin complex of the cell cycle.

PLK represent a family of evolutionarily conserved Serin-/Threoninkinasen that promote the progression of the cell cycle. You have the enzyme number EC 2.7.11.21. Most species have only one form of PLK, humans are PLK1 to PLK5 known.

Structure

The polo-like kinases contain a conserved kinase domain at the N -terminus, and a catalytically non-active polo box domain near the C-terminus, which consists of one or two polo -box designs. Polo box dimers bind the peptide sequence Ser - ( pSer-/pTyr ) - ( P / X), so allowing protein -protein interactions and to control the location as well as the substrate binding of the kinase in the cell, for example by binding to mitotic structures such as the centrosome and spindle apparatus.

The Polo - box domain is found exclusively within the PLK family and is found in any other protein.

Effect

PLK mediate the transition from the G2 phase to the M phase during the cell cycle, activation of CDC25 and mitotic processes including Zentrosomenreifung, formation of the spindle apparatus, activation of the anaphase - promoting complex (APC ), chromosome migration and Aktinringbildung ( cytokinesis ). PLK1 the mammalian is involved in the regulation of major steps of cell division, DNA damage repair, and apoptosis will advance the cell cycle. The PLK3 is a multifunctional enzyme for 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

PLK1 is particularly for medical research is of great interest, since tumors often an over-expression of this kinase can be observed and PLK1 due to its proliferative effect contributes to tumor growth. A negative regulation of p53 by PLK1 was observed. PLK1 overexpression also sets various mitotic checkpoint override what the genome stability at risk. If PLK1 overexpression detected in a tumor, it means a worse prognosis for the patient.

Inhibition of PLK1 may be effected either by inhibition of the kinase domain, or by inhibition of polo box domain: During the selective inhibition of kinase domains due to great structural similarity of the active sites is not trivial, sets the occurring exclusively in PLK Polo - box domain attractive alternative target dar.

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

Klaus Strebhardt and colleagues from the University Hospital Frankfurt / M. found in RNAi experiments with Onkomäusen and cell cultures that cancer cells need to live on PLK necessarily healthy cells are not.