PLK1
Encyclopedia
Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme
that in humans is encoded by the PLK1 (polo-like kinase 1) gene
.
s and is 66kDa. In addition to the N-terminus kinase
domain, there are two conserved polo-box regions of 30 amino acids at the C-terminus. Kinase activity is regulated at least in part, by the polo-boxes that are functionally important for both auto-inhibition and subcellular localization
.
s. In early mitosis
, it associates with mitotic spindle
poles. A recombinant GFP-PLK1 protein localizes to centromere
/kinetochore
region, suggesting a possible role for chromosome separation.
and establishment of the bipolar spindle. Plk1 phosphorylates and activates cdc25C, a phosphatase
that dephosphorylates and activates the cyclinB/cdc2 complex. Plk phosphorylates and activates components of the APC. The APC, which is activated by Fizzy-Cdc20 family proteins, is a cell cycle ubiquitin-protein ligase (E3) that degrades mitotic cyclins, chromosomal proteins that maintain cohesion of sister chromatids
, and anaphase
inhibitors. Abnormal spindle (Asp), a Polo kinase substrate, is a microtubule
-associated protein essential for correct behavior of spindle poles and M-phase microtubules. Plk1 localizes to the central region of the spindle in late mitosis and associates with kinesin
-like protein CHO1/MKLP1. The homologous motor protein in Drosophila
is the pavarotti gene product (PAR).
Studies have shown that the loss of PLK1 expression can induce pro-apoptotic pathways and inhibit growth. Based on yeast and murine studies of meiosis
, human PLK1 may also have a regulatory function in meiosis. S. cerevisiae polo kinase CDC5 is required to phosphorylate and remove meiotic cohesion during the first cell division. In CDC5 depleted cells, kinetochores are bioriented during meiosis I, and Mam1, a protein essential for coorientation, fails to associate with kinetochores. CDC5 is believed to have roles in sister-kinetochore coorientation and chromosome segregation
during meiosis I.
cells. Aneuploidy
and tumorigenesis can also result from centrosome
abnormality, particularly centrosome amplification defects. Centrosome duplication and maturation regulated by Plk1 occurs from late S phase
to prophase. Abnormal centrosome amplification may lead to multipolar spindles
and results in unequal segregation of chromosomes.Plk1 overexpression also increases the centrosome size and/or centrosome number, which will also lead to improper segregation of chromosomes, aneuploidy, and tumorigenesis.
Oncogenic properties of PLK1 are believed to be due to its role in driving cell cycle
progression. Supporting evidence comes from the overexpression studies of PLK1 in NIH3T3 cell line. These cells become capable of forming foci and growing in soft agar
and more importantly, these cells can form tumors in nude mice
due to PLK1 overexpression.
PLK1 has also been linked to known pathways that are altered during the neoplastic transformation. Retinoblastoma
tumor suppressor
(RB) pathway activation results in the repression of PLK1 promoter in a SWI/SNF chromatin remodeling
complex dependent manner. In case of RB inactivation, PLK1 expression seems to be deregulated. This new finding suggests that PLK1 may be a target of the retinoblastoma tumor suppressor (RB) pathway.
Moreover, PLK1 seems to be involved in the tumor suppressor p53 related pathways. Evidence suggests that PLK1 can inhibit transactivation
and pro-apoptotic functions of p53 function by physical interaction and phosphorylation
.
drugs. Many colon and lung cancer
s are caused by K-RAS mutations. These cancers are dependent on PLK1. When PLK1 expression was silenced with RNA interference
in cell culture
, K-RAS cells were selectively killed, without harming normal cells.
with PSMA7
, PSMA6
, NUDC
, PSMA5
, PSMA3
, TSC1
, PIN1
, PSMB3
and CHEK2
. Structural analysis has been used to explain the broad specificity of PLK1.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the PLK1 (polo-like kinase 1) gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Structure
Plk1 consists of 603 amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s and is 66kDa. In addition to the N-terminus kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
domain, there are two conserved polo-box regions of 30 amino acids at the C-terminus. Kinase activity is regulated at least in part, by the polo-boxes that are functionally important for both auto-inhibition and subcellular localization
Subcellular localization
The cells of eukaryotic organisms are elaborately subdivided into functionally distinct membrane bound compartments. Some major constituents of eukaryotic cells are: extracellular space, cytoplasm, nucleus, mitochondria, Golgi apparatus, endoplasmic reticulum , peroxisome, vacuoles, cytoskeleton,...
.
Localization
During interphase, PLK1 localizes to centrosomeCentrosome
In cell biology, the centrosome is an organelle that serves as the main microtubule organizing center of the animal cell as well as a regulator of cell-cycle progression. It was discovered by Edouard Van Beneden in 1883...
s. In early mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
, it associates with mitotic spindle
Mitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
poles. A recombinant GFP-PLK1 protein localizes to centromere
Centromere
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come closest in contact. It is involved in cell division as the point of mitotic spindle attachment...
/kinetochore
Kinetochore
The kinetochore is the protein structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart....
region, suggesting a possible role for chromosome separation.
Cell cycle regulation
Plk1 is an early trigger for G2/M transition. Plk1 supports the functional maturation of the centrosome in late G2/early prophaseProphase
Prophase, from the ancient Greek πρό and φάσις , is a stage of mitosis in which the chromatin condenses into a highly ordered structure called a chromosome in which the chromatin becomes visible. This process, called chromatin condensation, is mediated by the condensin complex...
and establishment of the bipolar spindle. Plk1 phosphorylates and activates cdc25C, a phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
that dephosphorylates and activates the cyclinB/cdc2 complex. Plk phosphorylates and activates components of the APC. The APC, which is activated by Fizzy-Cdc20 family proteins, is a cell cycle ubiquitin-protein ligase (E3) that degrades mitotic cyclins, chromosomal proteins that maintain cohesion of sister chromatids
Sister chromatids
Sister chromatids are two identical copies of a chromatid connected by a centromere. Compare sister chromatids to homologous chromosomes, which are the two different copies of the same chromosome that diploid organisms inherit, one from each parent...
, and anaphase
Anaphase
Anaphase, from the ancient Greek ἀνά and φάσις , is the stage of mitosis or meiosis when chromosomes move to opposite poles of the cell....
inhibitors. Abnormal spindle (Asp), a Polo kinase substrate, is a microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
-associated protein essential for correct behavior of spindle poles and M-phase microtubules. Plk1 localizes to the central region of the spindle in late mitosis and associates with kinesin
Kinesin
A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule filaments, and are powered by the hydrolysis of ATP . The active movement of kinesins supports several cellular functions including mitosis, meiosis and transport of cellular...
-like protein CHO1/MKLP1. The homologous motor protein in Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
is the pavarotti gene product (PAR).
Studies have shown that the loss of PLK1 expression can induce pro-apoptotic pathways and inhibit growth. Based on yeast and murine studies of meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
, human PLK1 may also have a regulatory function in meiosis. S. cerevisiae polo kinase CDC5 is required to phosphorylate and remove meiotic cohesion during the first cell division. In CDC5 depleted cells, kinetochores are bioriented during meiosis I, and Mam1, a protein essential for coorientation, fails to associate with kinetochores. CDC5 is believed to have roles in sister-kinetochore coorientation and chromosome segregation
Chromosome segregation
Chromosome segregation is a step in cell reproduction or division, where chromosomes pair off with their similar homologous chromosome. In mitosis, a complete copy of each one is made. In meiosis, one chromosome from each pair migrates to opposite ends of the cell and the genes are split to make a...
during meiosis I.
Role in tumorigenesis
Plk1 is considered a proto-oncogene, whose overexpression is often observed in tumorTumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cells. Aneuploidy
Aneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
and tumorigenesis can also result from centrosome
Centrosome
In cell biology, the centrosome is an organelle that serves as the main microtubule organizing center of the animal cell as well as a regulator of cell-cycle progression. It was discovered by Edouard Van Beneden in 1883...
abnormality, particularly centrosome amplification defects. Centrosome duplication and maturation regulated by Plk1 occurs from late S phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
to prophase. Abnormal centrosome amplification may lead to multipolar spindles
Multipolar spindles
Multipolar spindles are spindle formations characteristic of cancer cells. Spindle formation is mostly conducted by the aster of the centrosome which it forms around itself...
and results in unequal segregation of chromosomes.Plk1 overexpression also increases the centrosome size and/or centrosome number, which will also lead to improper segregation of chromosomes, aneuploidy, and tumorigenesis.
Oncogenic properties of PLK1 are believed to be due to its role in driving cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
progression. Supporting evidence comes from the overexpression studies of PLK1 in NIH3T3 cell line. These cells become capable of forming foci and growing in soft agar
Agar
Agar or agar-agar is a gelatinous substance derived from a polysaccharide that accumulates in the cell walls of agarophyte red algae. Throughout history into modern times, agar has been chiefly used as an ingredient in desserts throughout Asia and also as a solid substrate to contain culture medium...
and more importantly, these cells can form tumors in nude mice
Nude mouse
A nude mouse is a laboratory mouse from a strain with a genetic mutation that causes a deteriorated or absent thymus, resulting in an inhibited immune system due to a greatly reduced number of T cells. The phenotype, or main outward appearance of the mouse is a lack of body hair, which gives it...
due to PLK1 overexpression.
PLK1 has also been linked to known pathways that are altered during the neoplastic transformation. Retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
tumor suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
(RB) pathway activation results in the repression of PLK1 promoter in a SWI/SNF chromatin remodeling
Chromatin remodeling
Chromatin remodeling is the enzyme-assisted movement of nucleosomes on DNA.This is performed by chromatin remodeling complexes like SWI/SNF , RSC and Imitation SWI complexes ....
complex dependent manner. In case of RB inactivation, PLK1 expression seems to be deregulated. This new finding suggests that PLK1 may be a target of the retinoblastoma tumor suppressor (RB) pathway.
Moreover, PLK1 seems to be involved in the tumor suppressor p53 related pathways. Evidence suggests that PLK1 can inhibit transactivation
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
and pro-apoptotic functions of p53 function by physical interaction and phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
.
Clinical significance
PLK1 is being studied as a target for cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
drugs. Many colon and lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
s are caused by K-RAS mutations. These cancers are dependent on PLK1. When PLK1 expression was silenced with RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
in cell culture
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...
, K-RAS cells were selectively killed, without harming normal cells.
Interactions
PLK1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with PSMA7
PSMA7
Proteasome subunit alpha type-7 is a protein that in humans is encoded by the PSMA7 gene.-Interactions:PSMA7 has been shown to interact with HIF1A and PLK1.-Further reading:...
, PSMA6
PSMA6
Proteasome subunit alpha type-6 is a protein that in humans is encoded by the PSMA6 gene.-Interactions:PSMA6 has been shown to interact with PLK1 and PSMA3.-Further reading:...
, NUDC
NUDC
Nuclear migration protein nudC is a protein that in humans is encoded by the NUDC gene.-Interactions:NUDC has been shown to interact with PLK1 and PAFAH1B1.-Further reading:...
, PSMA5
PSMA5
Proteasome subunit alpha type-5 is a protein that in humans is encoded by the PSMA5 gene.-Further reading:...
, PSMA3
PSMA3
Proteasome subunit alpha type-3 is a protein that in humans is encoded by the PSMA3 gene.-Interactions:PSMA3 has been shown to interact with PSMA6, PLK1, Zif268 and CRYAB.-Further reading:...
, TSC1
TSC1
Tuberous sclerosis protein 1, also known as TSC1 or hamartin, is a human protein and gene.- Function :This peripheral membrane protein was implicated as a tumor suppressor...
, PIN1
PIN1
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1 gene.-Interactions:PIN1 has been shown to interact with CSNK2A2, Casein kinase 2, alpha 1, Wee1-like protein kinase, FOXO4, CDC25C, CDC27, MYT1, PLK1, MPHOSPH1, DAB2, P53, PKMYT1, C-jun,...
, PSMB3
PSMB3
Proteasome subunit beta type-3 is a protein that in humans is encoded by the PSMB3 gene.-Further reading:...
and CHEK2
CHEK2
CHEK2 is the official symbol for the human gene CHK2 checkpoint homolog. It is located on the long arm of chromosome 22.-Function:The protein encoded by this gene, CHK2 a protein kinase that is activated in response to DNA damage and is involved in cell cycle arrest.In response to DNA damage and...
. Structural analysis has been used to explain the broad specificity of PLK1.