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"Lim, Dan"
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Tony Stark, Iron Man. Vol. 1, Self-made man
\"From the cusp's of tomorrow's dreams to the forefront of imagination, one man always soars on the cutting edge of adventure! Tony Stark is Iron Man. And Iron Man ... is an idea. Always changing. Always evolving. Now, Dan Slott and Valerio Schiti propel the ultimate self-made hero to new heights of inventiveness!\"--Back cover.
BOOK
Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery
Cell division: PLK1 and aurora A at the checkpoint
Polo-like kinase-1 (PLK1) is an essential mitotic kinase regulating multiple aspects of the cell division process. Here, activation of PLK1 is shown to occur before mitosis and to depend on phosphorylation by aurora-A kinase, facilitated by a cofactor Bora. The initial activation of PLK1 seems to be a primary function of aurora-A.
Polo-like kinase-1 (PLK1) is an essential mitotic kinase regulating multiple aspects of the cell division process. Activation of PLK1 is shown to occur before mitosis and to depend on phosphorylation by aurora-A kinase, facilitated by a cofactor Bora. The initial activation of PLK1 seems to be a primary function of aurora-A.
Polo-like kinase-1 (PLK1) is an essential mitotic kinase regulating multiple aspects of the cell division process
1
. Activation of PLK1 requires phosphorylation of a conserved threonine residue (Thr 210) in the T-loop of the PLK1 kinase domain, but the kinase responsible for this has not yet been affirmatively identified
2
,
3
,
4
,
5
,
6
. Here we show that in human cells PLK1 activation occurs several hours before entry into mitosis, and requires aurora A (AURKA, also known as STK6)-dependent phosphorylation of Thr 210. We find that aurora A can directly phosphorylate PLK1 on Thr 210, and that activity of aurora A towards PLK1 is greatly enhanced by Bora (also known as C13orf34 and FLJ22624), a known cofactor for aurora A (ref.
7
). We show that Bora/aurora-A-dependent phosphorylation is a prerequisite for PLK1 to promote mitotic entry after a checkpoint-dependent arrest. Importantly, expression of a PLK1-T210D phospho-mimicking mutant partially overcomes the requirement for aurora A in checkpoint recovery. Taken together, these data demonstrate that the initial activation of PLK1 is a primary function of aurora A.
Journal Article
Skaar : son of Hulk - the complete collection
Born in fire. Raised by monsters. Destined to smash! On an alien planet shattered by war, no one is stronger than Skaar -- the savage Son of Hulk! But as a warlord and a princess spread chaos through the wastelands, will Skaar save the puny survivors -- or eat them? Skaar seeks the mysterious Old Power, but can even he stop the coming of the Silver Surfer-and Galactus the Devourer? The soothsayers sing: One day, monsters will clash -- the boy will confront the man who abandoned him. When the Son of Hulk seeks vengeance on his father, will Earth be turned into Planet Skaar?
BOOK
Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel
Polo-like kinase 1 (Plk1) regulates multiple processes that are important for cell proliferation, and it is a promising anticancer drug target. Efforts to inhibit Plk1 function by disrupting interactions that are essential for its proper localization identify a high-affinity alkylated phosphopeptide ligand specific for Plk1.
We obtained unanticipated synthetic byproducts from alkylation of the δ
1
nitrogen (N3) of the histidine imidazole ring of the polo-like kinase-1 (Plk1) polo-box domain (PBD)-binding peptide PLHSpT. For the highest-affinity byproduct, bearing a C
6
H
5
(CH
2
)
8
– group, a Plk1 PBD cocrystal structure revealed a new binding channel that had previously been occluded. An N-terminal PEGylated version of this peptide containing a hydrolytically stable phosphothreonyl residue (pT) bound the Plk1 PBD with affinity equal to that of the non-PEGylated parent but showed markedly less interaction with the PBDs of the two closely related proteins Plk2 and Plk3. Treatment of cultured cells with this PEGylated peptide resulted in delocalization of Plk1 from centrosomes and kinetochores and in chromosome misalignment that effectively induced mitotic block and apoptotic cell death. This work provides insights that might advance efforts to develop Plk1 PBD-binding inhibitors as potential Plk1-specific anticancer agents.
Journal Article
Proteomic screen defines the Polo-box domain interactome and identifies Rock2 as a Plk1 substrate
Polo‐like kinase‐1 (Plk1) phosphorylates a number of mitotic substrates, but the diversity of Plk1‐dependent processes suggests the existence of additional targets. Plk1 contains a specialized phosphoserine–threonine binding domain, the Polo‐box domain (PBD), postulated to target the kinase to its substrates. Using the specialized PBD of Plk1 as an affinity capture agent, we performed a screen to define the mitotic Plk1‐PBD interactome by mass spectrometry. We identified 622 proteins that showed phosphorylation‐dependent mitosis‐specific interactions, including proteins involved in well‐established Plk1‐regulated processes, and in processes not previously linked to Plk1 such as translational control, RNA processing, and vesicle transport. Many proteins identified in our screen play important roles in cytokinesis, where, in mammalian cells, the detailed mechanistic role of Plk1 remains poorly defined. We go on to characterize the mitosis‐specific interaction of the Plk1‐PBD with the cytokinesis effector kinase Rho‐associated coiled–coil domain‐containing protein kinase 2 (Rock2), demonstrate that Rock2 is a Plk1 substrate, and show that Rock2 colocalizes with Plk1 during cytokinesis. Finally, we show that Plk1 and RhoA function together to maximally enhance Rock2 kinase activity
in vitro
and within cells, and implicate Plk1 as a central regulator of multiple pathways that synergistically converge to regulate actomyosin ring contraction during cleavage furrow ingression.
Journal Article
Polo-Like Kinase-1 Controls Aurora A Destruction by Activating APC/C-Cdh1
Polo-like kinase-1 (Plk1) is activated before mitosis by Aurora A and its cofactor Bora. In mitosis, Bora is degraded in a manner dependent on Plk1 kinase activity and the E3 ubiquitin ligase SCF-betaTrCP. Here, we show that Plk1 is also required for the timely destruction of its activator Aurora A in late anaphase. It has been shown that Aurora A destruction is controlled by the auxiliary subunit Cdh1 of the Anaphase-Promoting Complex/Cyclosome (APC/C). Remarkably, we found that Plk1-depletion prevented the efficient dephosphorylation of Cdh1 during mitotic exit. Plk1 mediated its effect on Cdh1, at least in part, through direct phosphorylation of the human phosphatase Cdc14A, controlling the phosphorylation state of Cdh1. We conclude that Plk1 facilitates efficient Aurora A degradation through APC/C-Cdh1 activation after mitosis, with a potential role for hCdc14A.
Journal Article
Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1
The Plk1 kinase is a major regulator of mitosis that is often overexpressed in human cancers. Studies on phosphopeptide inhibitors specific to the polo-box domain of Plk1 reveal the determinants for specificity and may provide insight into the development of new therapeutics targeting protein-protein interactions.
Polo-like kinase-1 (Plk1) has a pivotal role in cell proliferation and is considered a potential target for anticancer therapy. The noncatalytic polo-box domain (PBD) of Plk1 forms a phosphoepitope binding module for protein-protein interaction. Here, we report the identification of minimal phosphopeptides that specifically interact with the PBD of human PLK1, but not those of the closely related PLK2 and PLK3. Comparative binding studies and analyses of crystal structures of the PLK1 PBD in complex with the minimal phosphopeptides revealed that the C-terminal SpT dipeptide functions as a high-affinity anchor, whereas the N-terminal residues are crucial for providing specificity and affinity to the interaction. Inhibition of the PLK1 PBD by phosphothreonine mimetic peptides was sufficient to induce mitotic arrest and apoptotic cell death. The mode of interaction between the minimal peptide and PBD may provide a template for designing therapeutic agents that target PLK1.
Journal Article
Erratum: Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1
Nat. Struct. Mol. Biol. 16, 876–882 (2009); published online 13 July 2009; corrected after print 21 September 2010 In the version of this article initially published, two of the numbers shown in Table 1 had the wrong sign. The error has been corrected in the HTML and PDF versions of the article.
Journal Article
Cyber Officers Must Be Technical Experts Too
All these would attest to that infantry platoon leader's lack of technical expertise in the tactics, techniques and procedures of his warfighting domain; likewise for the inept cyber network defense manager. The senior cyber officer managing a piece of the DoD Information Network will better understand his organization and why his soldiers spend so much time writing Bro intrusion detection system rules, for example, if he himself knows how to perform that task. [...]while exact force composition cannot be discussed, open-source news suggests that existing training pipelines are insufficient to meet the technical demands of the operational force.
Trade Publication Article