Polo-like kinase

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Polo-like kinases (Plks) are regulatory serine/threonine kinases of the cell cycle involved in mitotic entry, mitotic exit, spindle formation, cytokinesis, and meiosis. [1] Only one Plk is found in the genomes of the fly Drosophila melanogaster (Polo), budding yeast (Cdc5) and fission yeast (Plo1). [1] Vertebrates and other animals, however, have many Plk family members including Plk1 (Xenopus Plx1), Plk2/Snk (Xenopus Plx2), Plk3/Prk/FnK (Xenopus Plx3), Plk4/Sak and Plk5. [1] Of the vertebrate Plk family members, the mammalian Plk1 has been most extensively studied. During mitosis and cytokinesis, Plks associate with several structures including the centrosome, kinetochores, and the central spindle.

Contents

Structure

The catalytic serine/threonine kinase domain of Plk is at the N-terminus of the polo-like kinase protein. [1] A regulatory domain containing two signature motifs, known as polo box domains, is located at the C-terminus. [1] The polo-box domain (PBD) helps with specificity of substrate and localizes Plk to specific mitotic structures during mitosis. [1] These include the centrosomes in early M phase, the spindle midzone in early and late anaphase and the midbody during cytokinesis. [2]

Regulation

Plks are controlled at the level of protein synthesis and degradation, by the action of upstream kinases and phosphatases, and by localization to specific subcellular structures. Plks are activated by phosphorylation within a short region of the catalytic domain called the T-loop (or activation loop), with several serine/threonine phosphorylation sites in the loop identified. [3] Polo-like kinase kinase 1 (Plkk1) and protein kinase A (PKA) have been shown to be able to phosphorylate Plk1 in vitro [4] . The polo-box domain (PBD) of Plk1 is a phosphopeptide-binding motif. [5] This means that in the absence of a phosphorylated ligand, the PBD interacts with the catalytic domain thereby preventing substrate binding or kinase activation. Occupancy of the PBD by an exogenous phosphopeptide ligand would then cause the release of the catalytic domain, which, together with phosphorylation on the T-loop, converts Plk to the active form. [6] On exit from mitosis, Plks are proteolytically degraded through the ubiquitin-proteasome pathway after coming in contact with the ubiquitin-ligase Anaphase Promoting Complex (APC). [7]

Mitosis

Plks have been found to cooperate with Cdks in the orchestration of cell division. Entry into M phase is controlled through the activation of cyclin-dependent kinase 1 (CDK1)–cyclin B, and Cdc25 is a phosphatase that dephosphorylates Cdk1 to promote mitotic entry. Plk1 binds to phosphorylated Cdc25 through its PBD. [8] Thus Plks can phosphorylate Cdc25 and thereby regulate Cdc25 and indirectly Cdk1. A study shows that phosphorylation of a serine residue (Ser198) within a nuclear-export signal of Cdc25 promotes the nuclear accumulation of Ccdc25 in humans. [9] PBD has high affinity for proteins already phosphorylated at certain serine/threonine sites. [3] This requires priming of substrates by Plk itself or other kinases such as Cdk1 to create a docking site. However, there could also be phosphorylation-independent structural aspects contributing to binding. Plo1 (the Plk found in fission yeast) is part of a positive-feedback loop that controls the expression of genes that are required for cell division.

Plk has also been shown to be needed at the G2/M transition. Spindle pole formation needs Plk1, and some proteins such as gamma-tubulin fail to recruit spindle poles in the absence of Plk1 for centrosome maturation. Several other potential Plk1 substrates and binding partners that are implicated in microtubule nucleation and dynamics have also been identified including the microtubule-severing protein katanin, [10] the microtubule-stabilizing protein TCTP [11] and the microtubule-destabilizing protein stathmin. [12]

Plk is also needed for successful chromosome separation and exit from mitosis. Plk cooperates with Cdk1 in the control of several APC subunits. [3] Human PLK1 phosphorylates early mitotic inhibitor 1 (EMI1), an inhibitor of the APC. [13] Impairment of Plk function generally interferes with the normal onset of anaphase, indicating that Plks contribute to the control of APC activity. Plk1 associates with kinetochores during mitosis. In the absence of Plk1 function, bipolar spindle formation does not occur and cells arrest in prometaphase owing to Spindle Assembly Checkpoint activation. Plk1 function may be important for relieving the inhibitory checkpoint signal. If so, Plk1 could contribute to the resumption of mitotic progression on complete attachment of all chromosomes to the spindle apparatus.

Meiosis

The fly and yeast models have revealed that Polo kinases coordinate the more complex pattern of chromosome segregation in meiosis. Budding yeast Cdc5 is required in meiosis I for the removal of cohesins from chromosome arms, for the co-orientation of homologous chromosomes, and for the resolution of crossovers. [14] Cdc5 (Plk found in budding yeast) directly phosphorylates the meiotic cohesin and promotes its dissociation from the chromosome arms to allow for recombination but not from the centromeric region in meiosis I. In some yeast cdc5 mutants, bipolar rather than monopolar attachment of the sister kinetochores occurs during meiosis I because a complex of proteins called monopolins fails to localize to the kinetochore. [15]

Cytokinesis

The involvement of Polo kinases in the process of cytokinesis was first shown in fission yeast, in which the overexpression of Plo1 drives septation at any stage of the cell cycle and plo1 mutants fail to septate. [16] A protein called Mid1 determines where the contractile ring forms has been shown to shuttle out of the nucleus due to phosphorylation of Plk. [17] Recent studies on the role of mammalian Plk1 in cytokinesis have also identified kinesin-related motor Mklp2 and dynein subcomponent NudC as potential substrates of Plk1 that interact with the PBD. [18] Both Mklp2 and NudC have associated motor-protein activity and both localize to the central spindle. PLK1 has been found to phosphorylate the centralspindlin subunit CYK4 at the spindle midzone, thereby allowing the recruitment of the Rho guanine nucleotide-exchange factor (GEF) ECT2 to promote RhoA activation and thus actomyosin contraction of the ring. [19]

See also

Related Research Articles

<span class="mw-page-title-main">Cytokinesis</span> Part of the cell division process

Cytokinesis is the part of the cell division process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division in mitosis and meiosis. During cytokinesis the spindle apparatus partitions and transports duplicated chromatids into the cytoplasm of the separating daughter cells. It thereby ensures that chromosome number and complement are maintained from one generation to the next and that, except in special cases, the daughter cells will be functional copies of the parent cell. After the completion of the telophase and cytokinesis, each daughter cell enters the interphase of the cell cycle.

<span class="mw-page-title-main">Spindle apparatus</span> Feature of biological cell structure

In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a process that produces genetically identical daughter cells, or the meiotic spindle during meiosis, a process that produces gametes with half the number of chromosomes of the parent cell.

<span class="mw-page-title-main">Telophase</span> Final stage of a cell division for eukaryotic cells both in mitosis and meiosis

Telophase is the final stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase are reversed. As chromosomes reach the cell poles, a nuclear envelope is re-assembled around each set of chromatids, the nucleoli reappear, and chromosomes begin to decondense back into the expanded chromatin that is present during interphase. The mitotic spindle is disassembled and remaining spindle microtubules are depolymerized. Telophase accounts for approximately 2% of the cell cycle's duration.

<span class="mw-page-title-main">Anaphase-promoting complex</span> Cell-cycle regulatory complex

Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.

Maturation-promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-Phase-promoting factor) is the cyclin-Cdk complex that was discovered first in frog eggs. It stimulates the mitotic and meiotic phases of the cell cycle. MPF promotes the entrance into mitosis (the M phase) from the G2 phase by phosphorylating multiple proteins needed during mitosis. MPF is activated at the end of G2 by a phosphatase, which removes an inhibitory phosphate group added earlier.

G<sub>2</sub> phase Second growth phase in the eukaryotic cell cycle, prior to mitosis

G2 phase, Gap 2 phase, or Growth 2 phase, is the third subphase of interphase in the cell cycle directly preceding mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated. G2 phase ends with the onset of prophase, the first phase of mitosis in which the cell’s chromatin condenses into chromosomes.

<span class="mw-page-title-main">Cell cycle checkpoint</span> Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

<span class="mw-page-title-main">Aurora kinase A</span> Protein-coding gene in the species Homo sapiens

Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.

<span class="mw-page-title-main">Aurora kinase B</span> Protein

Aurora kinase B is a protein that functions in the attachment of the mitotic spindle to the centromere.

<span class="mw-page-title-main">PLK1</span> Mammalian protein found in Homo sapiens

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 gene.

In enzymology, a polo kinase is a kinase enzyme i.e. one that catalyzes the chemical reaction

<span class="mw-page-title-main">PKMYT1</span> Protein-coding gene in the species Homo sapiens

Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase also known as Myt1 kinase is an enzyme that in humans is encoded by the PKMYT1 gene.

<span class="mw-page-title-main">MASTL</span> Protein-coding gene in the species Homo sapiens

MASTL is an official symbol provided by HGNC for human gene whose official name is micro tubule associated serine/threonine kinase like. This gene is 32,1 kbps long. This gene is also known as GW, GWL, THC2, MAST-L, GREATWALL. This is present in mainly mammalian cells like human, house mouse, cattle, monkey, etc. It is in the 10th chromosome of the mammalian nucleus. Recent studies have been carried on zebrafish and frogs. This gene encodes for the protein micro tubule associated serine/threonine kinase and its sub-classes.

<span class="mw-page-title-main">Wee1</span> Nuclear protein

Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe. Wee1 has a molecular mass of 96 kDa and is a key regulator of cell cycle progression. It influences cell size by inhibiting the entry into mitosis, through inhibiting Cdk1. Wee1 has homologues in many other organisms, including mammals.

A series of biochemical switches control transitions between and within the various phases of the cell cycle. The cell cycle is a series of complex, ordered, sequential events that control how a single cell divides into two cells, and involves several different phases. The phases include the G1 and G2 phases, DNA replication or S phase, and the actual process of cell division, mitosis or M phase. During the M phase, the chromosomes separate and cytokinesis occurs.

Cdc14 and Cdc14 are a gene and its protein product respectively. Cdc14 is found in most of the eukaryotes. Cdc14 was defined by Hartwell in his famous screen for loci that control the cell cycle of Saccharomyces cerevisiae. Cdc14 was later shown to encode a protein phosphatase. Cdc14 is dual-specificity, which means it has serine/threonine and tyrosine-directed activity. A preference for serines next to proline is reported. Many early studies, especially in the budding yeast Saccharomyces cerevisiae, demonstrated that the protein plays a key role in regulating late mitotic processes. However, more recent work in a range of systems suggests that its cellular function is more complex.

<span class="mw-page-title-main">Mad1</span>

Mad1 is a non-essential protein which in yeast has a function in the spindle assembly checkpoint (SAC). This checkpoint monitors chromosome attachment to spindle microtubules and prevents cells from starting anaphase until the spindle is built up. The name Mad refers to the observation that mutant cells are mitotic arrest deficient (MAD) during microtubule depolymerization. Mad1 recruits the anaphase inhibitor Mad2 to unattached kinetochores and is essential for Mad2-Cdc20 complex formation in vivo but not in vitro. In vivo, Mad1 acts as a competitive inhibitor of the Mad2-Cdc20 complex. Mad1 is phosphorylated by Mps1 which then leads together with other activities to the formation of the mitotic checkpoint complex (MCC). Thereby it inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C). Homologues of Mad1 are conserved in eukaryotes from yeast to mammals.

<span class="mw-page-title-main">G2-M DNA damage checkpoint</span>

The G2-M DNA damage checkpoint is an important cell cycle checkpoint in eukaryotic organisms that ensures that cells don't initiate mitosis until damaged or incompletely replicated DNA is sufficiently repaired. Cells with a defective G2-M checkpoint will undergo apoptosis or death after cell division if they enter the M phase before repairing their DNA. The defining biochemical feature of this checkpoint is the activation of M-phase cyclin-CDK complexes, which phosphorylate proteins that promote spindle assembly and bring the cell to metaphase.

Mitotic exit is an important transition point that signifies the end of mitosis and the onset of new G1 phase for a cell, and the cell needs to rely on specific control mechanisms to ensure that once it exits mitosis, it never returns to mitosis until it has gone through G1, S, and G2 phases and passed all the necessary checkpoints. Many factors including cyclins, cyclin-dependent kinases (CDKs), ubiquitin ligases, inhibitors of cyclin-dependent kinases, and reversible phosphorylations regulate mitotic exit to ensure that cell cycle events occur in correct order with fewest errors. The end of mitosis is characterized by spindle breakdown, shortened kinetochore microtubules, and pronounced outgrowth of astral (non-kinetochore) microtubules. For a normal eukaryotic cell, mitotic exit is irreversible.

In molecular biology, DCTN6 is that subunit of the dynactin protein complex that is encoded by the p27 gene. Dynactin is the essential component for microtubule-based cytoplasmic dynein motor activity in intracellular transport of a variety of cargoes and organelles.

References

  1. 1 2 3 4 5 6 Barr, Francis A., Herman HW Silljé, and Erich A. Nigg. "Polo-like kinases and the orchestration of cell division." Nature reviews Molecular cell biology5.6 (2004): 429-441.
  2. ↑ Fenton, Brian; Glover, David M. (1993). "A conserved mitotic kinase active at late anaphase—telophase in syncytial Drosophila embryos". Nature. 363 (6430): 637–40. Bibcode:1993Natur.363..637F. doi:10.1038/363637a0. PMID   8510757.
  3. 1 2 3 Archambault, Vincent, and David M. Glover. "Polo-like kinases: conservation and divergence in their functions and regulation." Nature reviews Molecular cell biology 10.4 (2009): 265-275.
  4. ↑ Qian, Y. W., Erikson, E. & Maller, J. L. Purification and cloning of a protein kinase that phosphorylates and activates the polo-like kinase Plx1. Science 282, 1701–1704 (1998).
  5. ↑ Elia, A. E., Cantley, L. C. & Yaffe, M. B. Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates. Science 299, 1228–1231 (2003).
  6. ↑ Xu, Jun; Shen, Chen; Wang, Tao; Quan, Junmin (September 2013). "Structural basis for the inhibition of Polo-like kinase 1". Nature Structural & Molecular Biology. 20 (9): 1047–1053. doi:10.1038/nsmb.2623. ISSN   1545-9985.
  7. ↑ Shirayama, M., Zachariae, W., Ciosk, R. & Nasmyth, K. The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20p/fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae. EMBO J. 17, 1336–1349 (1998).
  8. ↑ Kumagai, A. & Dunphy, W. G. Purification and molecular cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts. Science 273, 1377–1380 (1996).
  9. ↑ Toyoshima-Morimoto, F., Taniguchi, E. & Nishida, E. Plk1 promotes nuclear translocation of human Cdc25C during prophase. EMBO Rep. 3, 341–348 (2002).
  10. ↑ McNally, K. P., Buster, D. & McNally, F. J. Katanin-mediated microtubule severing can be regulated by multiple mechanisms. Cell Motil. Cytoskeleton 53, 337–349 (2002).
  11. ↑ Yarm, F. R. Plk phosphorylation regulates the microtubulestabilizing protein TCTP. Mol. Cell. Biol. 22, 6209–6221 (2002).
  12. ↑ Budde, P. P., Kumagai, A., Dunphy, W. G. & Heald, R. Regulation of Op18 during spindle assembly in Xenopus egg extracts. J. Cell Biol. 153, 149–158 (2001).
  13. ↑ Hansen, D. V., Loktev, A. V., Ban, K. H. & Jackson, P. K. Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFTrCP-dependent destruction of the APC inhibitor Emi1. Mol. Biol. Cell 15, 5623–5634 (2004).
  14. ↑ Alexandru, G., Uhlmann, F., Mechtler, K., Poupart, M. A. & Nasmyth, K. Phosphorylation of the cohesin subunit Scc1 by Polo/Cdc5 kinase regulates sister chromatid separation in yeast. Cell 105, 459–472 (2001).
  15. ↑ Clyne, R. K. et al. Polo-like kinase Cdc5 promotes chiasmata formation and cosegregation of sister centromeres at meiosis I. Nature Cell Biol. 5, 480–485 (2003).
  16. ↑ Mulvihill, D. P., Petersen, J., Ohkura, H., Glover, D. M. & Hagan, I. M. Plo1 kinase recruitment to the spindle pole body and its role in cell division in Schizosaccharomyces pombe. Mol. Biol. Cell 10, 2771–2785 (1999).
  17. ↑ Bahler, J. et al. Role of polo kinase and Mid1p in determining the site of cell division in fission yeast. J. Cell Biol. 143, 1603–1616 (1998).
  18. ↑ Neef, R. et al. Phosphorylation of mitotic kinesin-like protein 2 by polo-like kinase 1 is required for cytokinesis. J. Cell Biol. 162, 863–875 (2003).
  19. ↑ Yoshida, S. et al. Polo-like kinase Cdc5 controls the local activation of Rho1 to promote cytokinesis. Science 313, 108–111 (2006).
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