Within cis crosstalk lies the possibility for adjacent crosstalk (i.e., between residues that are close to one another in both the primary and tertiary structures) or distal crosstalk (i.e., between residues that are far apart in both the primary and tertiary structures) ( Figure 3A). For example, cis crosstalk refers to communication between modifications on the same protein ( Figure 3A). Several models have been proposed for histone crosstalk ( 3– 5), and they are readily applied to non-histone proteins as well ( Figure 3). In addition, we highlight key features of protein kinase substrate recognition, identify potential substrates for crosstalk between PRMT1 and Akt, and finally discuss future perspectives and the medical relevance of this type of crosstalk.Īlthough crosstalk between two or more PTMs has predominantly been studied within the context of chromatin biology ( 1, 2), as one would expect, this type of regulatory mechanism extends to non-histone proteins as well. In particular, we briefly discuss the concept of crosstalk and its roots in chromatin biology, provide several known examples of crosstalk between these modifications, and describe the biophysical reasoning for this communication. Given the implications of this hypothesis on both human cell signaling and disease, this review will mainly focus on crosstalk between these specific modifications. Given that these neighboring arginine and lysines are key substrate recognition elements for many protein kinases ( Figure 1), we hypothesize that crosstalk between serine/threonine phosphorylation and arginine/lysine modifications ( Figure 2) is a general mechanism to regulate eukaryotic cell signaling. In recent years, several papers have been published that describe crosstalk in non-histone proteins, with a particular set of crosstalk examples involving serine/threonine phosphorylation and the modification of neighboring arginine and lysine residues. Generally, this crosstalk is thought to fine-tune cell signaling cascades such that a desired outcome is achieved, e.g., transcription of a particular gene or, alternatively, activation of one gene under the control of a transcription factor and repression of another. Over the last decade there have been several examples of crosstalk between two or more different post-translational modifications (PTMs), with many of these being observed within the context of histones. In addition, we predict likely examples of crosstalk between protein arginine methyltransferases 1 (PRMT1) and Akt, and discuss the future implications of these findings. In this review, we discuss several recent examples of non-histone kinase consensus sequence crosstalk, as well as provide the biophysical basis for these observations. Therefore, we hypothesize that non-histone crosstalk between serine/threonine phosphorylation and arginine/lysine modifications is a global mechanism for the modulation of cellular signaling. Interestingly, many kinase consensus sequences contain critical arginine/lysine residues surrounding the substrate serine/threonine residue. Recently, however, non-histone crosstalk has been observed between serine/threonine phosphorylation and the modification of arginine and lysine residues within kinase consensus sequences. These examples demonstrate the critical roles that crosstalk plays in regulating cell signaling pathways. The best characterized examples of crosstalk between two or more different post-translational modifications (PTMs) occur with respect to histones.
0 kommentar(er)
