Post-Translational Modification (PTM) Crosstalk Signaling Pathway
Pathway Description:Post-translational modifications (PTMs) have recently emerged as major regulators of protein function. Originally described in histones, these various chemical modifications (methylation, acetylation, phosphorylation, sumoylation, and more) have now been identified in nonhistone proteins as well. Early work defined a putative role for each of these modifications; for instance, acetylation correlates with activation and methylation with repression. However, more recent studies indicate that some of these modifications could trigger either activation or silencing in a context-dependent manner. For instance, methylation of histone H3 Lys9 correlates with repression, while methylation of H3 Lys4 correlates with activation. Furthermore, each of these moieties can be either mono-, di-, or tri-methylated, and depending on the degree of methylation, the biological output will be completely different. We now know that these PTMs are strictly established and maintained by a set of “writers” (histone methyltrans- ferases, acetyltransferases, etc.) and “erasers” (histone demethylases, deaceatylases, etc.) that define the different modifications found in our cells. Until recently, PTMs were considered independently, under the assumption that their functions would not be related to one another. It is now clear that PTMs work in concert, and the crosstalk between different modifications determines the final biological read out. In this context, some modifications can influence others, and it appears that specific combinations of these modifications can form a dynamic code. We provide a few examples of this type of crosstalk here. As shown, PTMs can be recognized by “readers” in cis, with a single protein using two different domains to recognize two specific modifications, as well as in trans, where modifications in one histone molecule could be recognized by a particular “reader” to modify another histone, in turn recruiting further readers in a step-wise manner. Further, in some cases, these modifications are themselves recognized by writers and erasers that could then modify neighbor moieties, in this way adjusting the code. Although there are now many examples of these functional networks, it is likely that we have just begun to scratch the surface. Better antibodies and novel technologies will help to complete this crosstalk puzzle, for which the specific fine-tuning appears critical to determine life as we know it.
- Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447(7143), 407–12.
- Gardner KE, Allis CD, Strahl BD (2011) Operating on chromatin, a colorful language where context matters. J. Mol. Biol. 409(1), 36–46.
- Lee JS, Smith E, Shilatifard A (2010) The language of histone crosstalk. Cell 142(5), 682–5.
- Musselman CA, Kutateladze TG (2011) Handpicking epigenetic marks with PHD fingers. Nucleic Acids Res. 39(21), 9061–71.
- Yang XJ, Seto E (2008) Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol. Cell 31(4), 449–61.
created May 2009
revised September 2012