© Federation of European Biochemical Societies
Edited By: Richard Perham
Impact Factor: 4.25
ISI Journal Citation Reports © Ranking: 2012: 74/290 (Biochemistry & Molecular Biology)
Online ISSN: 1742-4658
Virtual Issue Reversible Tyrosine Phospharylation Introduction
I have included two series of Minireviews. The first, presented by members of the European PTPNET consortium, provides an excellent foundation for those interested in the structure, regulation and function of the PTPs. The second describes various aspects of the role of the epidermal growth factor receptor (EGFR) in tumorigenesis, including discussion of EGFR-targetted therapies. The importance of disruption of tyrosine phoshorylation-dependent signalling to the etiology of disease, and ways in which such aberrant signalling may be targetted therapeutically, are currently a major focus of research in this area. Continuing the theme of EGFR family members, Takeuchi et al explore the interplay between the phosphatase MKP-1 and the JNK MAP kinase in regulating apoptosis induced by the EGFR inhibitor AG1478. Nagashima et al explore the effects of the EGFR inhibitor Iressa on transcription, including the role of MIG6 as a negative regulator of EGFR signalling. The review by De Lorenzo and D’Alessio, and the paper by Troise et al, examine the effects of immunotherapeutics, such as Herceptin, on the function of another EGFR family member, HER2/ERBB2, which is associated with breast cancer. It is important to note, however, that there is more to this area than just EGFR! Bonaventure et al examine mutations in FGFR3 in skeletal dysplasia, Inder et al explore the role of viral VEGF molecules from parapoxviruses, which exert their effects via activation of VEGFR PTKs in host cells and Ha et al report on the effects of GM-CSF, which acts through JAK PTKs, on proliferation of fibroblast-like synoviocytes in rheumatoid arthritis.
Like the PTPs, the PTKs exist in both transmembrane receptor-like and non-transmembrane forms. The prototypic PTK, SRC, is a member of the latter group. As would be expected for enzymes that exert such profound effects on cell function, the activity of both the PTKs and PTPs is tightly controlled in vivo. Kaimachniko and Kholodenko present a mathematical model to explain the complexities of regulation of SRC by phosphorylation/dephosphorylation. Vacaru and den Hertog also explore the regulation of SRC, but from the perspective of the receptor PTP, PTPα. This functional interaction illustrates the complexity of the interplay between PTKs and PTPs in the regulation of cell signalling. By dephosphorylating the inhibitory C-terminal phosphorylation site in SRC PTPα can, somewhat counter-intuitively, act positively to stimulate SRC activity, promote tyrosine phosphorylation and enhance signalling. An example of the regulatory interplay between individual PTKs, SRC and CDK4, is presented by Martin et al. Papers describing additional mechanisms for control of PTK function have been included, such as transcriptional regulation, illustrated by the effects of NF-κB on transcription of the gene encoding the PTK TEC (Yu et al), and the importance of protein-protein interactions regulating the PTK FYN directly (Solheim et al) and the PTK RET indirectly, through restricting its location to defined sub-cellular compartments (Lundgren et al). Sanchez-Gonzalez et al review an interesting mechanism by which interaction between EGFR and calmodulin may underlie a mechanism for cross-talk between tyrosine phosphorylation and Ca2+-dependent signals. Tight control is also exerted over the PTPs. Dilaver et al describe the contribution of proteolytic processing to determining the complexity of expression of different isoforms of PTPBR7, encoded by the PTPRR gene, which are targetted to distinct subcellular locations. These observations emphasize further the importance of compartmentalization in regulation of signalling. Recently, a new tier of control over tyrosine phosphorylation has been described that is exerted through reversible oxidation and inactivation of members of the PTP family in response to a wide array of physiological stimuli. Lou et al use mass spectrometry to demonstrate that the majority of PTP1B is subjected to this mode of regulation in cancer cells. Trumpler et al demonstrate that irreversible oxidation of PTP1B may render it prone to cleavage by calpain. A further role for reversible oxidation in regulating the dimerization, and thereby the signalling function, of receptor PTPs is described by Groen et al.
The preceding discussion has focused on enzymes that recognize tyrosyl residues exclusively, however, within the families of PTKs and PTPs are enzymes that are described as being of “dual specificity”. Although they have the capacity to recognize Ser/Thr, as well as Tyr residues in proteins, in reality they can be more specific in their function in vivo. The kinase DYRK1A, which has been implicated in Down’s syndrome, autophosphorylates on a Tyr residue in the activation loop, but recognizes Ser/Thr residues in target substrates. Seifert et al and Gockler et al investigate the function of this enzyme and its inhibition by the naturally occurring small molecule, harmine. Among the PTP family, cdc14 is an intriguing dual specificity phosphatase (DSP) that regulates the cell cycle by dephosphorylating targets of cyclin-dependent kinases as substrates. Angelika Amon has been a leader in the study of cdc14 and I have included a review in which she presents a personal perspective on the characterization of this enzyme. Schwertassek et al present a characterization of the importance of myristoylation of the DSP JSP-1, which promotes activation of the MAP kinase JNK, illustrating a new aspect of the control of MAP kinase signalling and apoptosis.
Although much has been discovered, this remains a vibrant field. Many PTKs and PTPs are known primarily by their sequence, with their functional importance still to be described fully. Warner et al and Davis et al illustrate how characterization of peptide substrates of the ephrin receptor PTKs can be used to provide insights into the mechanism of action and potential physiological function of these enzymes. Finally, the characterization of non-coding RNAs is revolutionizing the way we think about genomic regulation. Perhaps not unexpectedly, links between signal transduction and non-coding RNA function are being established. In this context, Terasawa et al and Wang et al report on the identification of microRNAs (miRNAs), which regulate translation, as downstream targets of tyrosine phosphorylation-dependent signalling pathways. Terasawa et al examine miRNA function in the regulation of NGF-dependent cell survival and Wang et al examine the regulation of miR-125a-5p expression in response to EGF and its potential role in lung cancer. I think these latter papers illustrate that in this field new frontiers are being identified, and extended, continually. I hope that this collection of papers will provide a snapshot of what is an exciting time in signal transduction research.
Papers Selected by Nicholas K. Tonks