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Protein Phosphorylation in Health and Disease
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Protein Phosphorylation in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 24320

Special Issue Editors

Prof. Dr. Maria Ruzzene

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Padova, Padova, Italy
Interests: signal transduction; cell signaling; signaling pathways; protein phosphorylation; protein kinases; protein phosphatases; protein kinase inhibitors; cancer biology; proteins; apoptosis; cell death; cancer research; cancer cell line
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Sandra Marmiroli

E-Mail Website
Guest Editor
Department of Biomedical, Metabolic and Neuronal Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
Interests: cellular signaling; lipid-activated protein kinases; identification of isoform-specific substrates of the AKT protein kinase; modulation of glycolytic vs. oxidative cellular phenotypes by signaling pathways in acute leukemia models; definition of the phosphorylome of primary blast cells from leukemia patients, and its modulation by the PI3K pathway; kinase-inhibitor therapy in hematological malignancies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Phosphorylation is the most common mechanism of signal transduction regulation in eukaryotic cells. It is generally held that not less than 30% of the total proteome corresponds to proteins undergoing phosphorylation during their lifespan. They are targets of a concerted action played by protein kinases and phosphatases, which ensures that phosphate resides on each target site (Ser, Thr or Tyr) exactly for the time required to transmit the signal. It follows that any perturbation of this balance might result in even dramatic consequences. A deep knowledge of the physiological phosphorylation-dependent processes, under healthy conditions, is therefore mandatory to better recognize any pathological alteration. This is particularly relevant considering that only the identification of the molecular and biochemical bases of a pathology will allow to make progress towards successful therapeutic strategies.

This Special Issue of IJMS intends to contribute to this field, collecting recent findings and review articles on:

  • the biochemistry of phosphorylation (kinome, phospho-proteome, novel substrates/sites/regulation/ functions)
  • the correlation between diseases and aberrant kinase/phosphatase activities;
  • the phosphorylation of specific disease-related proteins;
  • novel drugs and/or therapeutic strategies based on targeting kinases/phosphatases/substrates.

Prof. Dr. Maria Ruzzene
Prof. Dr. Sandra Marmiroli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • phosphorylation
  • protein kinase
  • protein phosphatase
  • aberrant signalling
  • diseases
  • drug target
  • phospho-substrate
  • phospho-proteome
  • kinome
  • cell signaling
  • phosphorylome
  • protein kinase inhibitors
  • kinase inhibitor therapy

Published Papers (5 papers)

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Research

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11 pages, 1443 KiB  
Article
KSIMC: Predicting Kinase–Substrate Interactions Based on Matrix Completion
by Jingzhong Gan, Jie Qiu, Canshang Deng, Wei Lan, Qingfeng Chen and Yanling Hu
Int. J. Mol. Sci. 2019, 20(2), 302; https://doi.org/10.3390/ijms20020302 - 14 Jan 2019
Cited by 3 | Viewed by 3434
Abstract
Protein phosphorylation is an important chemical modification catalyzed by kinases. It plays important roles in many cellular processes. Predicting kinase–substrate interactions is vital to understanding the mechanism of many diseases. Many computational methods have been proposed to identify kinase–substrate interactions. However, the prediction [...] Read more.
Protein phosphorylation is an important chemical modification catalyzed by kinases. It plays important roles in many cellular processes. Predicting kinase–substrate interactions is vital to understanding the mechanism of many diseases. Many computational methods have been proposed to identify kinase–substrate interactions. However, the prediction accuracy still needs to be improved. Therefore, it is necessary to develop an efficient computational method to predict kinase–substrate interactions. In this paper, we propose a novel computational approach, KSIMC, to identify kinase–substrate interactions based on matrix completion. Firstly, the kinase similarity and substrate similarity are calculated by aligning sequence of kinase–kinase and substrate–substrate, respectively. Then, the original association network is adjusted based on the similarities. Finally, the matrix completion is used to predict potential kinase–substrate interactions. The experiment results show that our method outperforms other state-of-the-art algorithms in performance. Furthermore, the relevant databases and scientific literature verify the effectiveness of our algorithm for new kinase–substrate interaction identification. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Health and Disease)
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14 pages, 1534 KiB  
Article
Possible Involvement of 2′,3′-Cyclic Nucleotide-3′-Phosphodiesterase in the Protein Phosphorylation-Mediated Regulation of the Permeability Transition Pore
by Yulia Baburina, Irina Odinokova, Tamara Azarashvili, Vladimir Akatov, Linda Sotnikova and Olga Krestinina
Int. J. Mol. Sci. 2018, 19(11), 3499; https://doi.org/10.3390/ijms19113499 - 07 Nov 2018
Cited by 10 | Viewed by 2600
Abstract
Calcium as a secondary messenger regulates the phosphorylation of several membrane-bound proteins in brain and liver mitochondria. Regulation of the activity of different protein kinases and phosphatases by Ca2+ occurs through its binding with calmodulin. The protein phosphorylation is strongly dependent on [...] Read more.
Calcium as a secondary messenger regulates the phosphorylation of several membrane-bound proteins in brain and liver mitochondria. Regulation of the activity of different protein kinases and phosphatases by Ca2+ occurs through its binding with calmodulin. The protein phosphorylation is strongly dependent on the Ca2+-induced mitochondrial permeability transition pore (mPTP) opening. 2′,3′-Cyclic nucleotide-3′-phosphodiesterase (CNPase) was phosphorylated by protein kinases A and C. CNPase and melatonin (MEL) might interact with calmodulin. The effects of the calmodulin antagonist calmidazolium and the inhibitor of protein kinase A H89 on mPTP opening in rat brain mitochondria of male Wistar rats were investigated. In addition, the role of CNPase, serine/threonine kinases, and MEL in the mPTP opening was examined. The anti-CNPase antibody added to rat brain mitochondria (RBM) reduced the content of CNPase in mitochondria. The threshold [Ca2+] decreased, and mitochondrial swelling was accelerated in the presence of the anti-CNPase antibody. H89 enhanced the effect of anti-CNPase antibody and accelerated the swelling of mitochondria, while CmZ abolished the effect of anti-CNPase antibody under mPTP opening. The levels of phospho-Akt and phospho-GSK3β increased, while the MEL content did not change. It can be assumed that CNPase may be involved in the regulation of these kinases, which in turn plays an important role in mPTP functioning. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Health and Disease)
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Review

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16 pages, 2512 KiB  
Review
Mutation-Driven Signals of ARID1A and PI3K Pathways in Ovarian Carcinomas: Alteration Is An Opportunity
by Pradip De and Nandini Dey
Int. J. Mol. Sci. 2019, 20(22), 5732; https://doi.org/10.3390/ijms20225732 - 15 Nov 2019
Cited by 9 | Viewed by 3639
Abstract
The chromosome is a functionally dynamic structure. The dynamic nature of chromosome functionally connects it to almost every event within a cell, in health and sickness. Chromatin remodeling system acts in unison with the cell survival pathway in mediating a variety of cellular [...] Read more.
The chromosome is a functionally dynamic structure. The dynamic nature of chromosome functionally connects it to almost every event within a cell, in health and sickness. Chromatin remodeling system acts in unison with the cell survival pathway in mediating a variety of cellular functions, including mitosis, differentiation, DNA damage repair, and apoptosis. In humans, the 16 SWI/SNF complexes are a class of nucleosome remodelers, and ARID1A, an epigenetic tumor suppressor, is a member of mammalian 17 chromatin remodeling complex, SWI/SNF. Alterations of chromatin remodeling system contribute to tumorigenic events in various cancers, including ovarian cancers. Oncogenic changes of genes of the PI3K pathway are one of the potential genetic determinants of ovarian carcinomas. In this review, we present the data demonstrating the co-occurrence of mutations of ARID1A and the PI3K pathway in our cohort of ovarian cancers from the Avera Cancer Institute (SD, USA). Taking into account data from our cohort and the cBioPortal, we interrogate the opportunity provided by this co-occurrence in the context of mutation-driven signals in the life cycle of a tumor cell and its response to the targeted anti-tumor drugs. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Health and Disease)
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17 pages, 1843 KiB  
Review
The Role of Tyrosine Phosphorylation of Protein Kinase C Delta in Infection and Inflammation
by Qingliang Yang, Jordan C. Langston, Yuan Tang, Mohammad F. Kiani and Laurie E. Kilpatrick
Int. J. Mol. Sci. 2019, 20(6), 1498; https://doi.org/10.3390/ijms20061498 - 26 Mar 2019
Cited by 33 | Viewed by 6522
Abstract
Protein Kinase C (PKC) is a family composed of phospholipid-dependent serine/threonine kinases that are master regulators of inflammatory signaling. The activity of different PKCs is context-sensitive and these kinases can be positive or negative regulators of signaling pathways. The delta isoform (PKCδ) is [...] Read more.
Protein Kinase C (PKC) is a family composed of phospholipid-dependent serine/threonine kinases that are master regulators of inflammatory signaling. The activity of different PKCs is context-sensitive and these kinases can be positive or negative regulators of signaling pathways. The delta isoform (PKCδ) is a critical regulator of the inflammatory response in cancer, diabetes, ischemic heart disease, and neurodegenerative diseases. Recent studies implicate PKCδ as an important regulator of the inflammatory response in sepsis. PKCδ, unlike other members of the PKC family, is unique in its regulation by tyrosine phosphorylation, activation mechanisms, and multiple subcellular targets. Inhibition of PKCδ may offer a unique therapeutic approach in sepsis by targeting neutrophil-endothelial cell interactions. In this review, we will describe the overall structure and function of PKCs, with a focus on the specific phosphorylation sites of PKCδ that determine its critical role in cell signaling in inflammatory diseases such as sepsis. Current genetic and pharmacological tools, as well as in vivo models, that are used to examine the role of PKCδ in inflammation and sepsis are presented and the current state of emerging tools such as microfluidic assays in these studies is described. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Health and Disease)
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14 pages, 1805 KiB  
Review
Cell Metabolism Control Through O-GlcNAcylation of STAT5: A Full or Empty Fuel Tank Makes a Big Difference for Cancer Cell Growth and Survival
by Manuel Rauth, Patricia Freund, Anna Orlova, Stefan Grünert, Nikola Tasic, Xiaonan Han, Hai-Bin Ruan, Heidi A. Neubauer and Richard Moriggl
Int. J. Mol. Sci. 2019, 20(5), 1028; https://doi.org/10.3390/ijms20051028 - 27 Feb 2019
Cited by 13 | Viewed by 7298
Abstract
O-GlcNAcylation is a post-translational modification that influences tyrosine phosphorylation in healthy and malignant cells. O-GlcNAc is a product of the hexosamine biosynthetic pathway, a side pathway of glucose metabolism. It is essential for cell survival and proper gene regulation, mirroring the metabolic status [...] Read more.
O-GlcNAcylation is a post-translational modification that influences tyrosine phosphorylation in healthy and malignant cells. O-GlcNAc is a product of the hexosamine biosynthetic pathway, a side pathway of glucose metabolism. It is essential for cell survival and proper gene regulation, mirroring the metabolic status of a cell. STAT3 and STAT5 proteins are essential transcription factors that can act in a mutational context-dependent manner as oncogenes or tumor suppressors. They regulate gene expression for vital processes such as cell differentiation, survival, or growth, and are also critically involved in metabolic control. The role of STAT3/5 proteins in metabolic processes is partly independent of their transcriptional regulatory role, but is still poorly understood. Interestingly, STAT3 and STAT5 are modified by O-GlcNAc in response to the metabolic status of the cell. Here, we discuss and summarize evidence of O-GlcNAcylation-regulating STAT function, focusing in particular on hyperactive STAT5A transplant studies in the hematopoietic system. We emphasize that a single O-GlcNAc modification is essential to promote development of neoplastic cell growth through enhancing STAT5A tyrosine phosphorylation. Inhibition of O-GlcNAcylation of STAT5A on threonine 92 lowers tyrosine phosphorylation of oncogenic STAT5A and ablates malignant transformation. We conclude on strategies for new therapeutic options to block O-GlcNAcylation in combination with tyrosine kinase inhibitors to target neoplastic cancer cell growth and survival. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Health and Disease)
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