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Non-histone protein methylation as a regulator of cellular signalling and function

Key Points

  • Approximately 4,000 Lys and Arg methylation sites have been identified in human proteins to date, most of which are on non-histone proteins.

  • The mapping of methyltransferase–substrate networks indicated that a large array of cellular functions is regulated by protein methylation, ranging from chromatin structure remodelling to gene transcription, DNA repair, protein synthesis, RNA metabolism, cell cycle progression, apoptosis and signal transduction.

  • Crosstalk often occurs between phosphorylation and methylation, and between two neighbouring methylated residues. This may result in the enhancement or repression of protein function and cellular processes.

  • Methylation has emerged as an important modulator of cell signalling. Lys or Arg methylation of regulatory proteins in the MAPK, WNT, BMP, Hippo and JAK–STAT signalling pathways were shown to modulate signalling sensitivity, strength, or duration.

  • Methylation signals on histone and non-histone proteins may regulate each other to affect nuclear processes. Proteins that contain a methyl-lysine- or methylarginine-binding domain often function as hubs of signalling integration or diversification. Examples are found in the regulation of nuclear factor-κB and p53 transcriptional activity by methylation.

  • The size of the methylproteome may be as large as that of the tyrosine phosphoproteome. Advances in mass spectrometry and related technologies are speeding up the characterization of the methylproteome and the elucidation of its functions in health and disease.

Abstract

Methylation of Lys and Arg residues on non-histone proteins has emerged as a prevalent post-translational modification and as an important regulator of cellular signal transduction mediated by the MAPK, WNT, BMP, Hippo and JAK–STAT signalling pathways. Crosstalk between methylation and other types of post-translational modifications, and between histone and non-histone protein methylation frequently occurs and affects cellular functions such as chromatin remodelling, gene transcription, protein synthesis, signal transduction and DNA repair. With recent advances in proteomic techniques, in particular mass spectrometry, the stage is now set to decode the methylproteome and define its functions in health and disease.

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Figure 1: Lys and Arg methylation.
Figure 2: Methyltransferase–substrate networks.
Figure 3: Regulation of protein function by PTM crosstalk.
Figure 4: Regulation of cellular signalling pathways by protein methylation.
Figure 5: Integration of histone and non-histone protein methylation signals in DNA double-strand break repair.

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References

  1. Ambler, R. P. & Rees, M. W. Epsilon-N-methyl-lysine in bacterial flagellar protein. Nature 184, 56–57 (1959).

    Article  CAS  PubMed  Google Scholar 

  2. Murray, K. The occurrence of epsilon-N-methyl lysine in histones. Biochemistry 3, 10–15 (1964).

    Article  CAS  PubMed  Google Scholar 

  3. Burnett, G. & Kennedy, E. P. The enzymatic phosphorylation of proteins. J. Biol. Chem. 211, 969–980 (1954).

    CAS  PubMed  Google Scholar 

  4. Eckhart, W., Hutchinson, M. A. & Hunter, T. An activity phosphorylating tyrosine in polyoma T antigen immunoprecipitates. Cell 18, 925–933 (1979).

    CAS  PubMed  Google Scholar 

  5. Strahl, B. & Allis, C. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Greer, E. L. & Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nature Rev. Genet. 13, 343–357 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Zhou, V. W., Goren, A. & Bernstein, B. E. Charting histone modifications and the functional organization of mammalian genomes. Nature Rev. Cancer 12, 7–18 (2011).

    Article  CAS  Google Scholar 

  8. Berger, S. L. The complex language of chromatin regulation during transcription. Nature 447, 407–412 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Esteller, M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nature Rev. Genet. 8, 286–298 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Fuks, F. DNA methylation and histone modifications: teaming up to silence genes. Curr. Opin. Genet. Dev. 15, 490–495 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Paik, W. K., Paik, D. C. & Kim, S. Historical review: the field of protein methylation. Trends Biochem. Sci. 32, 146–152 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Lake, A. N. & Bedford, M. T. Protein methylation and DNA repair. Mutat. Res. 618, 91101 (2007).

    Article  CAS  Google Scholar 

  15. Smith, B. C. & Denu, J. M. Chemical mechanisms of histone lysine and arginine modifications. Biochim. Biophys. Acta 1789, 45–57 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bedford, M. T. & Richard, S. Arginine methylation: an emerging regulator of protein function. Mol. Cell 18, 263–272 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Chen, C., Nott, T. J., Jin, J. & Pawson, T. Deciphering arginine methylation: Tudor tells the tale. Nature Rev. Mol. Cell. Biol. 12, 629–642 (2011).

    Article  CAS  Google Scholar 

  18. Moran, M. F. et al. Src homology region 2 domains direct protein-protein interactions in signal transduction. Proc. Natl Acad. Sci. USA 87, 8622–8626 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Marengere, L. E. . et al. SH2 domain specificity and activity modified by a single residue. Nature 369, 502–505 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Zhou, M. M. et al. Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 PTB domain. Nature Struct. Biol. 3, 388–393 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Zheng, Y. et al. Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nature 499, 166–171 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lu, R. & Wang, G. G. Tudor: a versatile family of histone methylation 'readers'. Trends Biochem. Sci. 38, 546–555 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Black, J. C., Van Rechem, C. & Whetstine, J. R. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol. Cell. 48, 491–507 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Lachner, M. et al. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Gayatri, S. & Bedford, M. T. Readers of histone methylarginine marks. Biochim. Biophys. Acta 1839, 702–710 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kachirskaia, I. et al. Role for 53BP1 tudor domain recognition of p53 dimethylated at lysine 382 in DNA damage signaling. J. Biol. Chem. 283, 34660–34666 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huang, J. et al. p53 is regulated by the lysine demethylase LSD1. Nature 449, 105–108 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Spannhoff, A. et al. The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. Chem. Med. Chem. 4, 1568–1582 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Arrowsmith, C. H. et al. Epigenetic protein families: a new frontier for drug discovery. Nature Rev. Drug Discov. 11, 384–400 (2012).

    Article  CAS  Google Scholar 

  31. Yang, Y. & Bedford, M. T. Protein arginine methyltransferases and cancer. Nature Rev. Cancer 13, 37–50 (2013).

    Article  CAS  Google Scholar 

  32. Salcini, A. E. et al. Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins. Oncogene 9, 2827–2836 (1994).

    CAS  PubMed  Google Scholar 

  33. Steen, H., Kuster, B., Fernandez, M., Pandey, A. & Mann, M. Tyrosine phosphorylation mapping of the epidermal growth factor receptor signalling pathway. J. Biol. Chem. 277, 1031–1039 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Zhang, G. et al. Mass spectrometry mapping of epidermal growth factor receptor phosphorylation related to oncogenic mutations and tyrosine kinase inhibitor sensitivity. J. Proteome Res. 10, 305–319 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Greer, E. L. et al. A histone methylation network regulates transgenerational epigenetic memory in C. elegans. Cell Rep. 7, 113–126 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Valekunja, U. K. et al. Histone methyltransferase MLL3 contributes to genome-scale circadian transcription. Proc. Natl Acad. Sci. USA 110, 1554–1559 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dhami, G. K. et al. Dynamic methylation of Numb by Set8 regulates its binding to p53 and apoptosis. Mol. Cell 50, 565–576 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Liu, H. et al. A method for systematic mapping of protein lysine methylation identifies functions for HP1β in DNA damage response. Mol. Cell. 50, 723–735 (2013). This paper describes a novel method for identifying Lys-methylated proteins that combines chromodomain pull-down, peptide arrays, bioinformatics and mass spectrometry.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Carlson, S. M. et al. Proteome-wide enrichment of proteins modified by lysine methylation. Nature Protoc. 9, 37–50 (2014).

    Article  CAS  Google Scholar 

  40. Lee, T. Y. et al. Identification and characterization of lysine-methylated sites on histones and non histone proteins. Comput. Biol. Chem. 50, 11–18 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Xie, Q. et al. Methylation-mediated regulation of E2F1 in DNA damage-induced cell death. J. Recept. Signal Transduct. Res. 31, 139–146 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Levy, D. et al. Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling. Nature Immunol. 12, 29–36 (2011).

    Article  CAS  Google Scholar 

  43. Botuyan, M. V. et al. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127, 1361–1373 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mazur, P. K. et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510, 283–287 (2014). This paper reports that Lys methylation can positively regulate MAPK signaling in K-RAS dependent cancers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Boisvert, F. M., Rhe, A., Richard, S. & Doherty, A. J. The GAR motif of 53BP1 is arginine methylated by PRMT1 and is necessary for 53BP1 DNA binding activity. Cell Cycle 4, 1834–1841 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406–411 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Tuzon, C. T. et al. Concerted activities of distinct H4K20 methyltransferases at DNA double-strand breaks regulate 53BP1 nucleation and NHEJ-directed repair. Cell Rep. 8, 430–438 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sanders, S. L. et al. Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell 119, 603–614 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Choudary, C. et al. The growing landscape of lysine acetylation links metabolism and cell signaling. Nature Rev. Mol. Cell. Biol. 15, 536–550 (2014).

    Article  CAS  Google Scholar 

  50. Gou, A. et al. Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol. Cell Proteom. 13, 372–387 (2014).

    Article  CAS  Google Scholar 

  51. Hornbeck, P. V. et al. PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res. 40, D261–D270 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Moore, K. E. et al. A general molecular affinity strategy for global detection and proteomic analysis of lysine methylation. Mol. Cell 50, 444–456 (2013). This study describes the use of the 3xMBT methyl-binding domain to enrich Lys-methylated proteins for identification by mass spectrometry.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bremang, M. et al. Mass spectrometry-based identification and characterization of lysine and arginine methylation in the human proteome. Mol. Biosyst. 9, 2231–2247 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Cao, X. J., Arnaudo, A. M. & Garcia, B. A. Large-scale global identification of protein lysine methylation in vivo. Epigenetics 8, 477–485 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ong, S. E., Mittler, G. & Mann, M. Identifying and quantifying in vivo methylation sites by heavy methyl SILAC. Nature Methods 1, 119–126 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Wang, H. et al. Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. Mol. Cell 8, 1207–1217 (2002).

    Article  Google Scholar 

  57. Tachibana, M. et al. Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J. Biol. Chem. 276, 25309–25317 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Wang, H. et al. Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 293, 853–857 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Dhayalan, A., Kudithipudi, S., Rathert, P. & Jeltsch, A. Specificity analysis-based identification of new methylation targets of the SET7/9 protein lysine methyltransferase. Chem. Biol. 18, 111–120 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Kwak, Y. T. et al. Methylation of SPT5 regulates its interaction with RNA polymerase II and transcriptional elongation properties. Mol. Cell 11, 1055–1066 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Rho, J., Choi, S., Jung, C. R. & Im, D. S. Arginine methylation of Sam68 and SLM proteins negatively regulates their poly(U) RNA binding activity. Arch. Biochem. Biophys. 466, 49–57 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Swiercz, R., Cheng, D., Kim, D. & Bedford, M. T. Ribosomal protein rpS2 is hypomethylated in PRMT3-deficient mice. J. Biol. Chem. 282, 16917–16923 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Carr, S. M. et al. Interplay between lysine methylation and Cdk phosphorylation in growth control by the retinoblastoma protein. EMBO J. 30, 317–327 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Martin, G. et al. Arginine methylation in subunits of mammalian pre-mRNA cleavage factor I. RNA 16, 1646–1659 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Moore, K. E. & Gozani, O. An unexpected journey: Lysine methylation across the proteome. Biochim. Biophys. Acta http://dx.doi.org/10.1016/j.bbagrm.2014.02.008 (2014).

  66. Zhao, Y., Brickner, J. R., Majid, M. C. & Mosammaparast, N. Crosstalk between ubiquitin and other post-translational modifications on chromatin during double-strand break repair. Trends Cell. Biol. 24, 426–434 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yamagata, K. et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol. Cell 32, 221–231 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Sabbattini, P. et al. An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation. Mol. Biol. Cell. 25, 904–915 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Esteve, P. O. et al. A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability. Nature Struct. Mol. Biol. 18, 42–48 (2011).

    Article  CAS  Google Scholar 

  70. Lawrence, T. The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb. Perspect. Biol. 1, a001651 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Duran, A. et al. Essential role of RelA Ser311 phosphorylation by ζPKC in NF-κB transcriptional activation. EMBO J. 22, 3910–3918 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chang, Y. et al. Structural basis of SETD6-mediated regulation of the NF-κB network via methyl-lysine signaling. Nucleic Acids Res. 39, 6380–6389 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tachibana, M. et al. Histone methyltransferases G9a and GLP form hetermeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev. 19, 815–826 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Munro, S. et al. Lysine methylation regulates the pRb tumour suppressor protein. Oncogene 29, 2357–2367 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Fischle, W. et al. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438, 1116–1122 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Kokura, K., Sun, L., Bedford, M. T. & Fang, J. Methyl-H3K9-binding protein MPP8 mediates E-cadherin gene silencing and promotes tumour cell motility and invasion. EMBO J. 26, 3678–3687 (2009).

    Google Scholar 

  77. Rothbart, S. B. et al. Associated of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation. Nature Struct. Mol. Biol. 19, 1155–1160 (2012).

    Article  CAS  Google Scholar 

  78. Migliori, V., Phalke, S., Bezzi, M. & Guccione, E. Arginine/lysine-methyl/methyl switches: biochemical role of histone arginine methylation in transcriptional regulation. Epigenomics 2, 119–137 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Dai, C. & Gu, W. P53 post-translational modification: deregulation in tumorigenesis. Trends Mol. Med. 16, 528–536 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Jansson, M. et al. Arginine methylation regulates the p53 response. Nature Cell. Biol. 10, 1431–1439 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Marouco, D., Garabadgiu, A. V., Melino, G. & Barlev, N. A. Lysine specific modifications of p53: a matter of life and death? Oncotarget 4, 1556–1571 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Greeson, N. T. et al. Di-methyl H4 lysine 20 targets the checkpoint protein Crb2 to sites of DNA damage. J. Biol. Chem. 283, 33168–33174 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Huang, J. et al. Repression of p53 activity by Smyd2-mediated methylation. Nature 444, 629–632 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Chuikov, S. et al. Regulation of p53 activity through lysine methylation. Nature 432, 353–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Roy, S. et al. Structural insight into p53 recognition by the 53BP1 tandem Tudor domain. J. Mol. Biol. 398, 489–496 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. West, L. E. et al. The MBT repeats of L3MBTL1 link SET8-mediated p53 methylation at lysine 382 to target gene repression. J. Biol. Chem. 285, 37725–37732 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cui, G. et al. PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53. Nature Struct. Mol. Biol. 19, 916–924 (2012).

    Article  CAS  Google Scholar 

  88. Shi, X. et al. Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol. Cell 27, 636–646 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sharma, A. et al. Mutant V599EB-Raf regulates growth and vasculas development of malignant melanoma tumors. Cancer Res. 65, 241202421 (2005).

    Google Scholar 

  90. Hoeflich, K. P. et al. Oncogenic BRAF is required for tumor growth and maintenance in melanoma models. Cancer Res. 66, 999–1006 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Andreu-Pérez, P. et al. Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. Sci Signal. 4, ra58 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hartsough, E. J. et al. Lysine methylation promotes VEGFR-2 activation and angiogenesis. Sci. Signal. 6, ra104 (2014). This study identifies Lys methylation of VEGFR2 as a means to modulate its kinase activity and the binding of downstream regulatory proteins.

    Article  CAS  Google Scholar 

  93. Hsu, J. M. et al. Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nature Cell. Biol. 13, 174–181 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Chen, D., Zhao, M. & Mundy, G. R. Bone morphogenetic proteins. Growth Factors 22, 233–241 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Xu, J. & Derynck, R. Does smad6 methylation control BMP signaling in cancer? Cell Cycle 13, 1209–1210 (2013).

    Article  CAS  Google Scholar 

  96. Mehra, A. & Wrana, J. L. TGF-β and the Smad signal transduction pathway. Biochem. Cell Biol. 80, 605–622 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Joiner, D. M., Ke, J., Zhong, Z., Xu, H. E. & Williams, B. O. LRP5 and LRP6 in development and disease. Trends Endocrinol. Metab. 24, 31–39 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. MacDonald, B. T. & He, X. Frizzled and LRP5/6 receptors for Wnt/β-catenin signaling. Cold Spring Harb. Perspect. Biol. 4, a007880 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wu, D. & Pan, W. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem. Sci. 35, 161–168 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Stamos, J. L. & Weis, W. L. The β-catenin destruction complex. Cold Spring Harb. Perspect. Biol. 5, a007898 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bikkavilli, R. K. & Malbon, C. C. Wnt3a-stimulated LRP6 phosphorylation is dependent upon arginine methylation of G3BP2. J. Cell Sci. 125, 2446–2456 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bikkavilli, R. K. et al. Dishevelled3 is a novel arginine methyl transferase substrate. Sci. Rep. 2, 805 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bikkavilli, R. K. & Malbon, C. C. Arginine methylation of G3BP1 in response to Wnt3a regulates β-catenin mRNA. J. Cell Sci. 124, 2310–2320 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhao, B., Tumaneng, K. & Guan, K. L. The hippo pathway is organ size control, tissue regeneration and stem cell self-renewal. Nature Cell Biol. 13, 877–883 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Zhoa, B. et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747–2761 (2007).

    Article  CAS  Google Scholar 

  106. Oudhoff, M. J. et al. Control of the hippo pathway by Set7-dependent methylation of Yap. Dev. Cell 26, 188–194 (2013). This study identifies the methylation of YAP by SETD7 as a checkpoint in the Hippo signalling pathway.

    Article  CAS  PubMed  Google Scholar 

  107. Tang, Y. & Tian, X. JAK-STAT3 and somatic cell reprogramming. JAKSTAT 2, e24935 (2013).

    PubMed  PubMed Central  Google Scholar 

  108. Kim, E. et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23, 839–852 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Park, I. H. & Li, C. Characterization of molecular recognition of STAT3 SH2 domain inhibitors through molecular simulation. J. Mol. Recognit. 24, 254–265 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Yang, J. et al. Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc. Natl Acad. Sci. USA 107, 21499–21504 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bannister, A. J. & Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 21, 381–395 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Price, B. D. & D'Andrea, A. D. Chromatin remodeling at DNA double-strand breaks. Cell 152, 1344–1354 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Panier, S. & Boulton, S. J. Double-strand break repair: 53BP1 comes into focus. Nature Rev. Mol. Cell. Biol. 15, 7–18 (2014).

    Article  CAS  Google Scholar 

  114. Davis, A. J. & Chen, D. J. DNA double strand break repair via non-homologous end-joining. Transl. Cancer. Res. 2, 130–143 (2013).

    CAS  PubMed  Google Scholar 

  115. Panier, S. & Durocher, D. Push back to respond better: regulatory inhibition of the DNA double-strand break response. Nature Rev. Mol. Cell. Biol. 14, 661–672 (2013).

    Article  CAS  Google Scholar 

  116. Acs, K. et al. The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks. Nature Struct. Mol. Biol. 18, 1345–1350 (2011).

    Article  CAS  Google Scholar 

  117. Mallette, F. A. et al. RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A trigger 53BP1 recruitment to DNA damage sites. EMBO J. 31, 1865–1878 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Polo, S. E. & Jackson, S. P. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 25, 409–433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Nowsheen, S. & Yang, E. S. The intersection between DNA damage response and cell death pathways. Exp. Oncol. 34, 243–254 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Reinhardt, H. C. & Schumacher, B. The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet. 28, 128–136 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Haupt, Y., Maya, R., Kazaz, A. & Oren, M. Mdm2 promotes the rapid degradation of p53. Nature 387, 296–299 (1997).

    Article  CAS  PubMed  Google Scholar 

  122. Colaluca, I. N. et al. NUMB controls p53 tumour suppressor activity. Nature 451, 76–80 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Abbas, T. et al. CRL4Cdt2 regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation. Mol. Cell 40, 9–21 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Oda, H. et al. Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage. Mol. Cell 40, 364–376 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Wilhelm, M. et al. Mass-spectrometry-based draft of the human proteome. Nature 509, 582–587 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Kim, M. S. et al. A draft map of the human proteome. Nature 509, 575–581 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Picotti, P. & Aebersold, R. Selected reaction monitoring-based proteomics: workflows, potential, pitfalls and future directions. Nature Methods 9, 555–566 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Aebersold, R. & Mann, M. Mass spectrometry-based proteomics. Nature 422, 198–207 (2004).

    Article  CAS  Google Scholar 

  129. Bisson, N. et al. Selected reaction monitoring mass spectrometry reveals the dynamics of signalling through the GRB2 adaptor. Nature Biotech. 29, 653–658.

    Article  CAS  PubMed  Google Scholar 

  130. Li, L. et al. Prediction of phosphotyrosine signaling networks using a scoring matrix-assisted ligand identification approach. Nucleic Acids Res. 36, 3262–3273 (2008).

    Google Scholar 

  131. Miller, M. L. et al. Linear motif atlas for phosphorylation-dependent signaling. Sci. Signal. 1, ra2 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Linding, R. et al. NetworKIN: a resource for exploring cellular phosphorylation networks. Nucleic Acids Res. 36, D695–D699 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. He, Y., Korboukh, I., Jin, J. & Huang, J. Targeting protein lysine methylation and demethylation in cancers. Acta Biochim. Biophys. Sin. 44, 70–79 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Varier, R. A. & Timmers, H. T. Histone lysine methylation and demethylation pathways in cancer. Biochim. Biophys. Acta. 1815, 75–89 (2011).

    CAS  PubMed  Google Scholar 

  135. Thinnes, C. C. et al. Targeting histone lysine demethylases — Progress, challenges, and the future. Biochim. Biophys. Acta. http://dx.doi.org/10.1016/j.bbagrm.2014.05.009 (2014)

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Acknowledgements

The authors apologize to those whose findings are relevant to this Review but could not be cited owing to space constraints. Work in the laboratory of S.S.-C.L. is supported by grants from the Canadian Cancer Society, the Ontario Research Fund (ORF) and the Canadian Institute of Health Research. K.K.B. is the recipient of a Natural Science and Engineering Council of Canada (NSERC) Postdoctoral Fellowship. S.S.-C.L. holds a Canada Research Chair in Functional Genomics and Cellular Proteomics.

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Non-histone Lys methylation (DOC 225 kb)

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Glossary

S-Adenosylmethionine

The methyl donor in numerous methylation reactions, including Lys and Arg methylation. It is generated by methionine adenosyltransferase from ATP and methionine.

Tudor domains

Modular methyl-binding domains that were originally identified in the Tudor protein of Drosophila melanogaster. The Tudor domains often exist in multiple copies in a protein, and they can bind methylated Lys or methylated Arg.

Chromodomain

A modular methyl-binding domain of 40–50 amino acids that is commonly found in proteins involved in chromatin remodelling.

MBT

The malignant brain tumour (MBT) domain is a protein module implicated in the binding of methylated histone tails. MBT domains are found in a number of nuclear proteins that are involved in transcriptional regulation.

Gly–Arg-rich motif

(GAR Motif). A motif (RGG/RG) thought to be involved in nucleic acid binding. The Arg residue within the motif is frequently methylated by protein Arg methyltransferases.

SRC homology 2 domain

(SH2 domain). A modular domain of 100 amino acids that binds specifically to phosphotyrosine-containing peptides or proteins. Human cells express 120 different SH2 domains, many of which are involved in regulating tyrosine kinase function and signal transduction.

Modular domains

Conserved parts of a protein sequence or structure that confer a particular function. These domains can also remain functional independent of the parent protein.

Multiple reaction monitoring

(MRM; also known as selective reaction monitoring (SRM)). This is a highly sensitive mass spectrometry method for the targeted quantification of proteins and peptides in complex biological samples. It monitors only specific product ions from a precursor ion (peptide), while filtering out other peptides.

Methyl-SILAC

A mass spectroscopy-based method for identifying and quantifying changes in Lys or Arg methylation using stable isotope labelling by amino acids in cell culture (SILAC). Cells are cultured with [13CD3]methionine, which is then converted to [13CD3]SAM and incorporated in vivo into methylation sites. The labelling of methylation sites by the heavy 13CD3-methyl group facilitates their identification and quantification by mass spectrometry.

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Biggar, K., Li, SC. Non-histone protein methylation as a regulator of cellular signalling and function. Nat Rev Mol Cell Biol 16, 5–17 (2015). https://doi.org/10.1038/nrm3915

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