Human Plk4 phosphorylates Cdc25C

Bonni, Sepal; Ganuelas, Melissa L.; Petrinac, Steve; Hudson, John W.

doi:10.4161/cc.7.4.5387

Cited by 21 publications

(22 citation statements)

References 12 publications

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“…One explanation is that the hybrid Kin4-PBD1, which could be targeted correctly to Plk1 substrates via PBD1, contained a Kin4 domain able, as Kin1 of SmPlk1, to phosphorylate Xenopus Cdc25. This hypothesis is in agreement with published data showing that human Plk4 can phosphorylate and exert an additional control on Cdc25C [58]. This information, together with the demonstration that SmSak transcripts, as those of SmPlk1 [23], were abundant in the large oocytes of the female ovary (ie, in cells that could tentatively be compared with stage VI Xenopus oocytes arrested at G2 of meiosis 1) (Figure 3) prompted us to reinvestigate the potential participation of SmSak in meiosis resumption, especially via its possible cooperation with SmPlk1.…”

Section: Discussionsupporting

confidence: 93%

SmSak, the Second Polo-Like Kinase of the Helminth Parasite Schistosoma mansoni: Conserved and Unexpected Roles in Meiosis

et al. 2012

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Polo-like kinases (Plks) are a family of conserved regulators of a variety of events throughout the cell cycle, expanded from one Plk in yeast to five Plks in mammals (Plk1-5). Plk1 is the best characterized member of the Plk family, homolog to the founding member Polo of Drosophila, and plays a major role in cell cycle progression by triggering G2/M transition. Plk4/Sak (for Snk (Serum-inducible kinase) akin kinase) is a unique member of the family, structurally distinct from other Plk members, with essential functions in centriole duplication. The genome of the trematode parasite Schistosoma mansoni contains only two Plk genes encoding SmPlk1 and SmSak. SmPlk1 has been shown already to be required for gametogenesis and parasite reproduction. In this work, in situ hybridization indicated that the structurally conserved Plk4 protein, SmSak, was largely expressed in schistosome female ovary and vitellarium. Expression of SmSak in Xenopus oocytes confirmed its Plk4 conserved function in centriole amplification. Moreover, analysis of the function of SmSak in meiosis progression of G2-blocked Xenopus oocytes indicated that, in contrast to SmPlk1, SmSak cannot induce G2/M transition in the absence of endogenous Plk1 (Plx1). Unexpectedly, meiosis progression was spontaneously observed in Plx1-depleted oocytes co-expressing SmSak and SmPlk1. Molecular interaction between SmSak and SmPlk1 was confirmed by co-immunoprecipitation of both proteins. These data indicate that Plk1 and Plk4 proteins have the potential to interact and cross-activate in cells, thus attributing for the first time a potential role of Plk4 proteins in meiosis/mitosis entry. This unexpected role of SmSak in meiosis could be relevant to further consider the function of this novel Plk in schistosome reproduction.

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Section: Discussionsupporting

confidence: 93%

SmSak, the Second Polo-Like Kinase of the Helminth Parasite Schistosoma mansoni: Conserved and Unexpected Roles in Meiosis

et al. 2012

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“…The loss-of-function of Plk4 causes a failure of cell division, possibly leading to aneuploidy and polyploidy, which may in turn contribute to tumorigenesis [171]. Plk4 interacts with proteins involved in the cellular response to DNA damage, such as p53 [175], Cdc25C [176], and Chk2 [177], suggesting that Plk4 may play an important role in the DNA damage response signaling [178]. Plk4 also binds to and phosphorylates p53 [173, 175, 178], possibly affecting protein stability and activity of p53 [178], although phosphorylation site(s) are currently unknown.…”

Section: Negative Regulation Of P53mentioning

confidence: 99%

Mitotic Kinases and p53 Signaling

Breuer

2012

Biochemistry Research International

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Mitosis is tightly regulated and any errors in this process often lead to aneuploidy, genomic instability, and tumorigenesis. Deregulation of mitotic kinases is significantly associated with improper cell division and aneuploidy. Because of their importance during mitosis and the relevance to cancer, mitotic kinase signaling has been extensively studied over the past few decades and, as a result, several mitotic kinase inhibitors have been developed. Despite promising preclinical results, targeting mitotic kinases for cancer therapy faces numerous challenges, including safety and patient selection issues. Therefore, there is an urgent need to better understand the molecular mechanisms underlying mitotic kinase signaling and its interactive network. Increasing evidence suggests that tumor suppressor p53 functions at the center of the mitotic kinase signaling network. In response to mitotic spindle damage, multiple mitotic kinases phosphorylate p53 to either activate or deactivate p53-mediated signaling. p53 can also regulate the expression and function of mitotic kinases, suggesting the existence of a network of mutual regulation, which can be positive or negative, between mitotic kinases and p53 signaling. Therefore, deciphering this regulatory network will provide knowledge to overcome current limitations of targeting mitotic kinases and further improve the results of targeted therapy.

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“…Other known substrates of PLK4 mediate centriolar satellite integrity (PCM1 (19)), trophoblast differentiation (HAND1 (33)), and cell motility (APR2 (34)). Additionally, CEP152 (28,35), CDC25C (36), CHK2 (37), and ECT2 (38) have been identified as PLK4 substrates, although the functions of these phosphorylation events remain unclear. Three previous studies have reported MS-based screens to identify PLK4 interactors.…”

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confidence: 99%

Polo-like kinase 4 maintains centriolar satellite integrity by phosphorylation of centrosomal protein 131 (CEP131)

Denu

Sass

Johnson

et al. 2019

Journal of Biological Chemistry

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Edited by Xiao-Fan WangThe centrosome, consisting of two centrioles surrounded by a dense network of proteins, is the microtubule-organizing center of animal cells. Polo-like kinase 4 (PLK4) is a Ser/Thr protein kinase and the master regulator of centriole duplication, but it may play additional roles in centrosome function. To identify additional proteins regulated by PLK4, we generated an RPE-1 human cell line with a genetically engineered "analog-sensitive" PLK4 AS , which genetically encodes chemical sensitivity to competitive inhibition via a bulky ATP analog. We used this transgenic line in an unbiased multiplex phosphoproteomic screen. Several hits were identified and validated as direct PLK4 substrates by in vitro kinase assays. Among them, we confirmed Ser-78 in centrosomal protein 131 (CEP131, also known as AZI1) as a direct substrate of PLK4. Using immunofluorescence microscopy, we observed that although PLK4-mediated phosphorylation of Ser-78 is dispensable for CEP131 localization, ciliogenesis, and centriole duplication, it is essential for maintaining the integrity of centriolar satellites. We also found that PLK4 inhibition or use of a nonphosphorylatable CEP131 variant results in dispersed centriolar satellites. Moreover, replacement of endogenous WT CEP131 with an S78D phosphomimetic variant promoted aggregation of centriolar satellites. We conclude that PLK4 phosphorylates CEP131 at Ser-78 to maintain centriolar satellite integrity.

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Human Plk4 phosphorylates Cdc25C

Cited by 21 publications

References 12 publications

SmSak, the Second Polo-Like Kinase of the Helminth Parasite Schistosoma mansoni: Conserved and Unexpected Roles in Meiosis

SmSak, the Second Polo-Like Kinase of the Helminth Parasite Schistosoma mansoni: Conserved and Unexpected Roles in Meiosis

Mitotic Kinases and p53 Signaling

Polo-like kinase 4 maintains centriolar satellite integrity by phosphorylation of centrosomal protein 131 (CEP131)

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