The structure of the cell cycle protein Cdc14 reveals a proline-directed protein phosphatase

Gray, Christopher H.

doi:10.1093/emboj/cdg348

Cited by 139 publications

(180 citation statements)

References 42 publications

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“…1C). This analysis is consistent with structural data (26) indicating that hCDC14A shares a common preference with cyclin-dependent kinases in being proline directed with a preference for lysine or arginine three residues after the phosphorylation site (25). The presence of proline residues at positions -1, -2, and +2 indicates that hCDC14A may also counteract other kinases such as ERK1/2 and glycogen synthase kinase 3 (GSK-3β) that emulate cyclin-dependent kinases in being proline-directed kinases yet have a preference for additional proline residues surrounding the phosphorylation site (www.phosphosite.org/).…”

Section: Phosphosupporting

confidence: 90%

Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm

Chen

Uddin

Hardt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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CDC14 is an essential dual-specificity phosphatase that counteracts CDK1 activity during anaphase to promote mitotic exit in Saccharomyces cerevisiae. Surprisingly, human CDC14A is not essential for cell cycle progression. Instead, it regulates cell migration and cell adhesion. Little is known about the substrates of hCDC14A and the counteracting kinases. Here, we combine phospho-proteome profiling and proximity-dependent biotin identification to identify hCDC14A substrates. Among these targets were actin regulators, including the tumor suppressor eplin. hCDC14A counteracts EGF-induced rearrangements of actin cytoskeleton by dephosphorylating eplin at two known extracellular signal-regulated kinase sites, serine 362 and 604. hCDC14A(PD) and eplin knockout cell lines exhibited down-regulation of E-cadherin and a reduction in alpha/beta-catenin at cell-cell adhesions. Reduction in the levels of hCDC14A and eplin mRNA is frequently associated with colorectal carcinoma and is correlated with poor prognosis. We therefore propose that eplin dephosphorylation by hCDC14A reduces actin dynamics to restrict tumor malignancy

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Section: Phosphosupporting

confidence: 90%

Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm

Chen

Uddin

Hardt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In any of these cases, the Cdc14 SPIs highlight the importance of phosphorylation of kinetochore proteins for mitosis and warrant further characterization of the role of phosphorylation in regulating kinetochore homeostasis. Because Cdc14 normally functions as a dimer, the catalytically inactive mutants may be capable of recruiting wild-type Cdc14 to the kinetochore (48,49). This would produce false-negatives in our screen; hence, it is possible that our list of sites affected by Cdc14 is an underrepresentation of all of the critical CDK sites at the kinetochore.…”

Section: Discussionmentioning

confidence: 99%

Synthetic physical interactions map kinetochore regulators and regions sensitive to constitutive Cdc14 localization

Ólafsson

Thorpe

2015

Proc. Natl. Acad. Sci. U.S.A.

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The location of proteins within eukaryotic cells is often critical for their function and relocation of proteins forms the mainstay of regulatory pathways. To assess the importance of protein location to cellular homeostasis, we have developed a methodology to systematically create binary physical interactions between a query protein and most other members of the proteome. This method allows us to rapidly assess which of the thousands of possible protein interactions modify a phenotype. As proof of principle we studied the kinetochore, a multiprotein assembly that links centromeres to the microtubules of the spindle during cell division. In budding yeast, the kinetochores from the 16 chromosomes cluster together to a single location within the nucleus. The many proteins that make up the kinetochore are regulated through ubiquitylation and phosphorylation. By systematically associating members of the proteome to the kinetochore, we determine which fusions affect its normal function. We identify a number of candidate kinetochore regulators, including the phosphatase Cdc14. We examine where within the kinetochore Cdc14 can act and show that the effect is limited to regions that correlate with known phosphorylation sites, demonstrating the importance of serine phospho-regulation for normal kinetochore homeostasis.T he relocation of proteins between cellular compartments underlies many regulatory pathways. For example, protein relocation underpins most cell-signaling pathways (1) and the establishment of cell polarity and asymmetric cell division both require highly specialized relocation of proteins within the cell (2). Furthermore, the aberrant localization of proteins underlies the pathology of a number of diseases (3). However, our understanding of the effect of relocalizing members of the proteome is limited to specific studies typically concerning individual proteins, and only a select few studies have globally monitored protein relocation (4, 5).One highly localized structure within the cell is the kinetochore, which in budding yeast forms a single megadalton complex (6-8). The kinetochore attaches chromosomes to the spindle microtubules to drive accurate chromosome segregation. The kinetochore consists of at least 60 unique gene products present in multiple copies that stretch from the specialized H3 histone subunit (Cse4, CENP-A in mammals) to the microtubule binding proteins of the Dam1 complex (9). Kinetochores normally assemble hierarchically from the centromere-bound proteins (10). Once assembled, the structural homeostasis of the kinetochore is regulated by proteins that are recruited to kinetochores. For example, the histone subunit Cse4 is tightly regulated by the E3 ubiquitin ligase Psh1, which is localized at centromeres. Psh1 prevents excessive Cse4 centromere loading via ubiquitylation-dependent degradation of Cse4 (and at noncentromeric regions) (11). Cse4 is also phosphorylated by Ipl1, likely to destabilize aberrant microtubule interactions and ensure correct sister chromosome biorientation (12...

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“…The Cdc14 phosphatase preferentially dephosphorylates proteins that are modified by proline-directed kinases, such as cdk1/cyclinB, and plays a key role in mitotic exit, suggesting that it may dephosphorylate PR-Set7 Mailand et al 2002;Gray et al 2003;Cho et al 2005). Since mammals express two Cdc14 isoforms, Cdc14A and Cdc14B, whose specific substrates are poorly defined, it was necessary to investigate both isoforms (Li et al 1997).…”

Section: Cdc14 Specifically and Directly Dephosphorylates Pr-set7 S29mentioning

confidence: 99%

Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression

Wu¹,

Wang²,

Kong³

et al. 2010

Genes Dev.

124

116

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Although the PR-Set7/Set8/KMT5a histone H4 Lys 20 monomethyltransferase (H4K20me1) plays an essential role in mammalian cell cycle progression, especially during G2/M, it remained unknown how PR-Set7 itself was regulated. In this study, we discovered the mechanisms that govern the dynamic regulation of PR-Set7 during mitosis, and that perturbation of these pathways results in defective mitotic progression. First, we found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase. The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC cdh1 -mediated ubiquitination of PR-Set7 and subsequent proteolysis. This event is important for proper mitotic progression, as constitutive phosphorylation of PR-Set7 resulted in a substantial delay between metaphase and anaphase. Collectively, we elucidated the molecular mechanisms that control PR-Set7 protein levels during mitosis, and demonstrated that its orchestrated regulation is important for normal mitotic progression.[Keywords: PR-Set7; APC; Cdk1; Cdc14; cell cycle; chromatin] Supplemental material is available at http://www.genesdev.org.

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The structure of the cell cycle protein Cdc14 reveals a proline-directed protein phosphatase

Cited by 139 publications

References 42 publications

Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm

Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm

Synthetic physical interactions map kinetochore regulators and regions sensitive to constitutive Cdc14 localization

Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression

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