Systematic analysis of the Plk-mediated phosphoregulation in eukaryotes

Substantial evidence has confirmed that Polo-like kinases (Plks) play a crucial role in a variety of cellular processes via phosphorylation-mediated signaling transduction. Identification of Plk phospho-binding proteins and phosphorylation substrates is fundamental for elucidating the molecular mechanisms of Plks. Here, we present an integrative approach for the analysis of Plk-specific phospho-binding and phosphorylation sites (p-sites) in proteins. From the currently available phosphoproteomic data, we predicted tens of thousands of potential Plk phospho-binding and phosphorylation sites in eukaryotes, respectively. Furthermore, statistical analysis suggested that Plk phospho-binding proteins are more closely implicated in mitosis than their phosphorylation substrates. Additional computational analysis together with in vitro and in vivo experimental assays demonstrated that human Mis18B is a novel interacting partner of Plk1, while pT14 and pS48 of Mis18B were identified as phospho-binding sites. Taken together, this systematic analysis provides a global landscape of the complexity and diversity of potential Plk-mediated phosphoregulation, and the prediction results can be helpful for further experimental investigation.

[1]  E. Salmon,et al.  The spindle-assembly checkpoint in space and time , 2007, Nature Reviews Molecular Cell Biology.

[2]  Steven P Gygi,et al.  Akt–RSK–S6 Kinase Signaling Networks Activated by Oncogenic Receptor Tyrosine Kinases , 2010, Science Signaling.

[3]  Tony Pawson,et al.  Specificity in Signal Transduction From Phosphotyrosine-SH2 Domain Interactions to Complex Cellular Systems , 2004, Cell.

[4]  P. Jallepalli,et al.  Combination of Chemical Genetics and Phosphoproteomics for Kinase Signaling Analysis Enables Confident Identification of Cellular Downstream Targets* , 2011, Molecular & Cellular Proteomics.

[5]  Thomas A Neubert,et al.  Identification of Phosphopeptides by MALDI Q-TOF MS in Positive and Negative Ion Modes after Methyl Esterification*S , 2005, Molecular & Cellular Proteomics.

[6]  Erich A Nigg,et al.  The crystal structure of the human polo‐like kinase‐1 polo box domain and its phospho‐peptide complex , 2003, The EMBO journal.

[7]  S. Gammeltoft,et al.  Proteomic screen defines the Polo‐box domain interactome and identifies Rock2 as a Plk1 substrate , 2007, The EMBO journal.

[8]  Xuebiao Yao,et al.  Aurora B kinase activation requires survivin priming phosphorylation by PLK1. , 2011, Journal of molecular cell biology.

[9]  Erich A. Nigg,et al.  Polo-like kinases and the orchestration of cell division , 2004, Nature Reviews Molecular Cell Biology.

[10]  Yusuke Toyoda,et al.  Priming of Centromere for CENP-A Recruitment by Human hMis18α, hMis18β, and M18BP1 , 2007 .

[11]  Tony Pawson,et al.  Defining the Specificity Space of the Human Src Homology 2 Domain*S , 2008, Molecular & Cellular Proteomics.

[12]  Zexian Liu,et al.  GPS-SNO: Computational Prediction of Protein S-Nitrosylation Sites with a Modified GPS Algorithm , 2010, PloS one.

[13]  E. Nishida,et al.  Identification of a Consensus Motif for Plk (Polo-like Kinase) Phosphorylation Reveals Myt1 as a Plk1 Substrate* , 2003, Journal of Biological Chemistry.

[14]  Yu Xue,et al.  GPS: a comprehensive www server for phosphorylation sites prediction , 2005, Nucleic Acids Res..

[15]  T. Pawson,et al.  Reading protein modifications with interaction domains , 2006, Nature Reviews Molecular Cell Biology.

[16]  Jay A. Tischfield,et al.  The novel mouse Polo-like kinase 5 responds to DNA damage and localizes in the nucleolus , 2010, Nucleic acids research.

[17]  Joel Dudley,et al.  MEGA: A biologist-centric software for evolutionary analysis of DNA and protein sequences , 2008, Briefings Bioinform..

[18]  Michele Pagano,et al.  The Cdc14B-Cdh1-Plk1 Axis Controls the G2 DNA-Damage-Response Checkpoint , 2008, Cell.

[19]  Yixue Li,et al.  SysPTM: A Systematic Resource for Proteomic Research on Post-translational Modifications* , 2009, Molecular & Cellular Proteomics.

[20]  Yu Xue,et al.  GPS 2.0, a Tool to Predict Kinase-specific Phosphorylation Sites in Hierarchy *S , 2008, Molecular & Cellular Proteomics.

[21]  Michael B. Yaffe,et al.  Scansite 2.0: proteome-wide prediction of cell signaling interactions using short sequence motifs , 2003, Nucleic Acids Res..

[22]  Allegra Via,et al.  Phospho.ELM: a database of phosphorylation sites—update 2008 , 2007, Nucleic Acids Res..

[23]  Christopher J. Wilkinson,et al.  The Polo kinase Plk4 functions in centriole duplication , 2005, Nature Cell Biology.

[24]  Osamu Iwasaki,et al.  Mis16 and Mis18 Are Required for CENP-A Loading and Histone Deacetylation at Centromeres , 2004, Cell.

[25]  Scott A Gerber,et al.  Large-scale phosphorylation analysis of alpha-factor-arrested Saccharomyces cerevisiae. , 2007, Journal of proteome research.

[26]  Steven P. Gygi,et al.  Large-scale phosphorylation analysis of mouse liver , 2007, Proceedings of the National Academy of Sciences.

[27]  References , 1971 .

[28]  J. Kornhauser,et al.  PhosphoSite: A bioinformatics resource dedicated to physiological protein phosphorylation , 2004, Proteomics.

[29]  Hsien-Da Huang,et al.  KinasePhos 2.0: a web server for identifying protein kinase-specific phosphorylation sites based on sequences and coupling patterns , 2007, Nucleic Acids Res..

[30]  Sandhya Rani,et al.  Human Protein Reference Database—2009 update , 2008, Nucleic Acids Res..

[31]  Yu Xue,et al.  MiCroKit 3.0: an integrated database of midbody, centrosome and kinetochore , 2009, Nucleic Acids Res..

[32]  Qi Zhu,et al.  PepCyber:P∼PEP: a database of human protein–protein interactions mediated by phosphoprotein-binding domains , 2007, Nucleic Acids Res..

[33]  Guy H. Grant,et al.  Computational Analysis of Phosphopeptide Binding to the Polo-Box Domain of the Mitotic Kinase PLK1 Using Molecular Dynamics Simulation , 2010, PLoS Comput. Biol..

[34]  Guoliang Chen,et al.  A genome‐wide analysis of sumoylation‐related biological processes and functions in human nucleus , 2005, FEBS letters.

[35]  Tony Pawson,et al.  Comparative Analysis Reveals Conserved Protein Phosphorylation Networks Implicated in Multiple Diseases , 2009, Science Signaling.

[36]  Andrew M. Fry,et al.  Coordinate Regulation of the Mother Centriole Component Nlp by Nek2 and Plk1 Protein Kinases , 2005, Molecular and Cellular Biology.

[37]  Rachael P. Huntley,et al.  The GOA database in 2009—an integrated Gene Ontology Annotation resource , 2008, Nucleic Acids Res..

[38]  Yu Xue,et al.  GPS: a novel group-based phosphorylation predicting and scoring method. , 2004, Biochemical and biophysical research communications.

[39]  P. Jackson,et al.  CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[40]  David M. Glover,et al.  Polo-like kinases: conservation and divergence in their functions and regulation , 2009, Nature Reviews Molecular Cell Biology.

[41]  Devin K Schweppe,et al.  Quantitative Phosphoproteomics Identifies Substrates and Functional Modules of Aurora and Polo-Like Kinase Activities in Mitotic Cells , 2011, Science Signaling.

[42]  Michael B Yaffe,et al.  The Polo-Box Domain: A Molecular Integrator of Mitotic Kinase Cascades and Polo-like Kinase Function , 2004, Cell cycle.

[43]  Michael B. Yaffe,et al.  The Molecular Basis for Phosphodependent Substrate Targeting and Regulation of Plks by the Polo-Box Domain , 2003, Cell.

[44]  Feng Zhang,et al.  The Plk1-dependent Phosphoproteome of the Early Mitotic Spindle* , 2010, Molecular & Cellular Proteomics.

[45]  Tien Hsu,et al.  RNA-dependent integrin α3 protein localization regulated by the Muscleblind-like protein MLP1 , 2005, Nature Cell Biology.

[46]  Xuegong Zhang,et al.  Prediction of kinase‐specific phosphorylation sites with sequence features by a log‐odds ratio approach , 2007, Proteins.

[47]  R. Karess,et al.  Rod-Zw10-Zwilch: a key player in the spindle checkpoint. , 2005, Trends in cell biology.

[48]  D. Higgins,et al.  See Blockindiscussions, Blockinstats, Blockinand Blockinauthor Blockinprofiles Blockinfor Blockinthis Blockinpublication Clustal: Blockina Blockinpackage Blockinfor Blockinperforming Multiple Blockinsequence Blockinalignment Blockinon Blockina Minicomputer Article Blockin Blockinin Blockin , 2022 .

[49]  Yu Xue,et al.  DOG 1.0: illustrator of protein domain structures , 2009, Cell Research.

[50]  Dongsup Kim,et al.  PostMod: sequence based prediction of kinase-specific phosphorylation sites with indirect relationship , 2010, BMC Bioinformatics.

[51]  J. Ferrell,et al.  Mechanisms of specificity in protein phosphorylation , 2007, Nature Reviews Molecular Cell Biology.

[52]  Xin Xu,et al.  Overexpression of PLK1 is associated with poor survival by inhibiting apoptosis via enhancement of survivin level in esophageal squamous cell carcinoma , 2009, International journal of cancer.

[53]  T. Hunter,et al.  The Protein Kinase Complement of the Human Genome , 2002, Science.

[54]  P. Bork,et al.  Systematic Discovery of In Vivo Phosphorylation Networks , 2007, Cell.

[55]  Ingrid Hoffmann,et al.  PLK2 phosphorylation is critical for CPAP function in procentriole formation during the centrosome cycle , 2010, The EMBO journal.

[56]  Otto Hudecz,et al.  Spatial Exclusivity Combined with Positive and Negative Selection of Phosphorylation Motifs Is the Basis for Context-Dependent Mitotic Signaling , 2011, Science Signaling.

[57]  Ruedi Aebersold,et al.  PhosphoPep—a database of protein phosphorylation sites in model organisms , 2008, Nature Biotechnology.

[58]  Michael B Yaffe,et al.  Structure and function of Polo-like kinases , 2005, Oncogene.

[59]  Akira Nakagawara,et al.  Polo-like Kinase 1 (Plk1) Inhibits p53 Function by Physical Interaction and Phosphorylation* , 2004, Journal of Biological Chemistry.

[60]  Ling Wang,et al.  Stress-induced c-Jun Activation Mediated by Polo-like Kinase 3 in Corneal Epithelial Cells* , 2007, Journal of Biological Chemistry.

[61]  Hanno Steen,et al.  Phosphorylation Analysis by Mass Spectrometry , 2006, Molecular & Cellular Proteomics.

[62]  Yusuke Toyoda,et al.  Priming of centromere for CENP-A recruitment by human hMis18alpha, hMis18beta, and M18BP1. , 2007, Developmental cell.

[63]  Andrew D. Sharrocks,et al.  Polo kinase controls cell-cycle-dependent transcription by targeting a coactivator protein , 2006, Nature.

[64]  Alma L. Burlingame,et al.  Widespread Protein Aggregation as an Inherent Part of Aging in C. elegans , 2010, PLoS biology.

[65]  T. Pawson,et al.  Assembly of Cell Regulatory Systems Through Protein Interaction Domains , 2003, Science.

[66]  Yu Xue,et al.  GPS 2.1: enhanced prediction of kinase-specific phosphorylation sites with an algorithm of motif length selection. , 2011, Protein engineering, design & selection : PEDS.

[67]  S. Mathivanan,et al.  A curated compendium of phosphorylation motifs , 2007, Nature Biotechnology.

[68]  Michael B Yaffe,et al.  Proteomic Screen Finds pSer/pThr-Binding Domain Localizing Plk1 to Mitotic Substrates , 2003, Science.

[69]  B. A. Ballif,et al.  ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage , 2007, Science.

[70]  Otto Hudecz,et al.  Quantitative Phospho-proteomics to Investigate the Polo-like Kinase 1-Dependent Phospho-proteome* , 2011, Molecular & Cellular Proteomics.