Direct interactions with both p27 and Cdk2 regulate Spy1-mediated proliferation<i>in vivo</i>and<i>in vitro</i>

Sorkhy, Mohammad Al; Fifield, Bre‐Anne; Myers, Dorothy; Porter, Lisa A.

doi:10.1080/15384101.2015.1121327

Cited by 13 publications

(11 citation statements)

References 32 publications

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“…For example, human Speedy A (Spy1) levels are tightly regulated during the proliferation of mammary progenitor cells, and are enriched in malignant human glioma cells, suggesting important roles for Speedy A in somatic cell cycle regulation in humans (31,32). The Cdkbinding Ringo domain of Speedy A is 98% identical in mice and humans (14).…”

Section: Discussionmentioning

confidence: 99%

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

Bayazit

Liu

et al. 2016

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

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Telomere attachment to the nuclear envelope (NE) is a prerequisite for chromosome movement during meiotic prophase I that is required for pairing of homologous chromosomes, synapsis, and homologous recombination. Here we show that Speedy A, a noncanonical activator of cyclin-dependent kinases (Cdks), is specifically localized to telomeres in prophase I male and female germ cells in mice, and plays an essential role in the telomere-NE attachment. Deletion of Spdya in mice disrupts telomere-NE attachment, and this impairs homologous pairing and synapsis and leads to zygotene arrest in male and female germ cells. In addition, we have identified a telomere localization domain on Speedy A covering the distal N terminus and the Cdk2-binding Ringo domain, and this domain is essential for the localization of Speedy A to telomeres. Furthermore, we found that the binding of Cdk2 to Speedy A is indispensable for Cdk2's localization on telomeres, suggesting that Speedy A and Cdk2 might be the initial components that are recruited to the NE for forming the meiotic telomere complex. However, Speedy A-Cdk2-mediated telomere-NE attachment is independent of Cdk2 activation. Our results thus indicate that Speedy A and Cdk2 might mediate the initial telomere-NE attachment for the efficient assembly of the telomere complex that is essential for meiotic prophase I progression. meiosis | telomere | Speedy A | Cdk2 | germ cells

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Section: Discussionmentioning

confidence: 99%

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

Bayazit

Liu

et al. 2016

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

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“…This work shows that Spy1 inhibits p27 levels in the absence and presence of Raf/Ras inhibitors (Figure 4A , hollow bars), demonstrating that this aspect of Spy1 activity is intact and that ERK-mediated effects reside downstream of p27 degradation. To investigate the importance of the direct Spy1-p27 interaction, a Spy1-p27 binding mutant (R170) was utilized [ 54 ]. Spy1-R170 prevents the downregulation of endogenous p27 seen with Spy1-WT as previously published (Figure 4B ) [ 54 ].…”

Section: Resultsmentioning

confidence: 99%

“…To investigate the importance of the direct Spy1-p27 interaction, a Spy1-p27 binding mutant (R170) was utilized [ 54 ]. Spy1-R170 prevents the downregulation of endogenous p27 seen with Spy1-WT as previously published (Figure 4B ) [ 54 ]. Interestingly, when cells were infected with R170 lentivirus there was no statistical increase in ERK phosphorylation as seen with Spy1-WT (Figure 4C and Supplementary Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

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The cyclin-like protein, SPY1, regulates the ERα and ERK1/2 pathways promoting tamoxifen resistance

Ferraiuolo

Tubman

Sinha³

et al. 2017

Oncotarget

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The Ras/Raf/MEK/ERK pathway conveys growth factor and mitogen signalling to control the phosphorylation of a plethora of substrates regulating proliferation, survival, and migration. The Ras signalling pathway is frequently associated with poor prognosis and drug resistance in various cancers including those of the blood, breast and prostate. Activation of the downstream effector ERK does not always occur via a linear cascade of events; complicating the targeting of this pathway therapeutically. This work describes a novel positive feedback loop where the cell cycle regulatory factor Spy1 (RINGO; gene SPDYA) activates ERK1/2 in a MEK-independent fashion. Spy1 was originally isolated for the ability to stimulate Xenopus oocyte maturation via a MAPK-signalling pathway and is known to override apoptosis triggered by the DNA damage response. We demonstrate that mammalian Spy1-mediated ERK activation increases ligand-independent phosphorylation and activation of estrogen receptor α, correlating with a decrease in tamoxifen sensitivity. This could define a novel druggable mechanism driving proliferation and resistance in select cancers.

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“…Accordingly, we find that unlike Cdk2‐CycA, Cdk2‐Spy1 is not inhibited by p27 and does not show preference for substrates that contain RxLF‐type docking motifs. Previous reports have demonstrated direct binding between Spy1 and p27 that depends on arginines within residues 170–180 of Spy1 (Porter et al , ; Al Sorkhy et al , ). In contrast, our structural data indicate that there is no direct interaction and that the association is mediated by Cdk.…”

Section: Discussionmentioning

confidence: 96%

Structural basis of divergent cyclin‐dependent kinase activation by Spy1/RINGO proteins

et al. 2017

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Cyclin-dependent kinases (Cdks) are principal drivers of cell division and are an important therapeutic target to inhibit aberrant proliferation. Cdk enzymatic activity is tightly controlled through cyclin interactions, posttranslational modifications, and binding of inhibitors such as the p27 tumor suppressor protein. Spy1/RINGO (Spy1) proteins bind and activate Cdk but are resistant to canonical regulatory mechanisms that establish cell-cycle checkpoints. Cancer cells exploit Spy1 to stimulate proliferation through inappropriate activation of Cdks, yet the mechanism is unknown. We have determined crystal structures of the Cdk2-Spy1 and p27-Cdk2-Spy1 complexes that reveal how Spy1 activates Cdk. We find that Spy1 confers structural changes to Cdk2 that obviate the requirement of Cdk activation loop phosphorylation. Spy1 lacks the cyclin-binding site that mediates p27 and substrate affinity, explaining why Cdk-Spy1 is poorly inhibited by p27 and lacks specificity for substrates with cyclin-docking sites. We identify mutations in Spy1 that ablate its ability to activate Cdk2 and to proliferate cells. Our structural description of Spy1 provides important mechanistic insights that may be utilized for targeting upregulated Spy1 in cancer.

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Direct interactions with both p27 and Cdk2 regulate Spy1-mediated proliferationin vivoandin vitro

Cited by 13 publications

References 32 publications

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

The cyclin-like protein, SPY1, regulates the ERα and ERK1/2 pathways promoting tamoxifen resistance

Structural basis of divergent cyclin‐dependent kinase activation by Spy1/RINGO proteins

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