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The Protein Journal Feb 2017Post translational modifications (PTMs) are involved in variety of cellular activities and phosphorylation is one of the most extensively studied PTM, which regulates a... (Review)
Review
Post translational modifications (PTMs) are involved in variety of cellular activities and phosphorylation is one of the most extensively studied PTM, which regulates a number of cellular functions like cell growth, differentiation, apoptosis and cell signaling in healthy condition. However, alterations in phosphorylation pathways result in serious outcomes in the form of diseases, especially cancer. Many signalling pathways including Tyrosine kinase, MAP kinase, Cadherin-catenin complex, Cyclin-dependent kinase etc. are major players of the cell cycle and deregulation in their phosphorylation-dephosphorylation cascade has been shown to be manifested in the form of various types of cancers. Tyrosine kinase family encompasses the greatest number of oncoproteins. MAPK cascade has an importance role in cancer growth and progression. Bcl-2 family proteins serve either proapoptotic or antiapoptotic function. Cadherin-catenin complex regulates cell adhesion properties and cyclins are the key regulators of cell cycle. Altered phosphorylations in any of the above pathways are strongly associated with cancer, at the same time they serve as the potential tergets for drug development against cancer. Drugs targeting tyrosine kinase are potent anticancer drugs. Inhibitors of MEK, PI3K and ERK signalling pathways are undergoing clinical trials. Thus, drugs targeting phosphorylation pathways represent a promising area for cancer therapy.
Topics: Animals; MAP Kinase Signaling System; Neoplasm Proteins; Neoplasms; Phosphorylation; Protein Kinase Inhibitors
PubMed: 28108801
DOI: 10.1007/s10930-017-9696-z -
Cell Reports Jul 2023Protein phosphorylation modification is crucial for signaling transduction in plant development and environmental adaptation. By precisely phosphorylating crucial... (Review)
Review
Protein phosphorylation modification is crucial for signaling transduction in plant development and environmental adaptation. By precisely phosphorylating crucial components in signaling cascades, plants can switch on and off the specific signaling pathways needed for growth or defense. Here, we have summarized recent findings of key phosphorylation events in typical hormone signaling and stress responses. More interestingly, distinct phosphorylation patterns on proteins result in diverse biological functions of these proteins. Thus, we have also highlighted latest findings that show how the different phosphosites of a protein, also named phosphocodes, determine the specificity of downstream signaling in both plant development and stress responses.
Topics: Phosphorylation; Signal Transduction; Plants; Plant Development; Plant Proteins
PubMed: 37405922
DOI: 10.1016/j.celrep.2023.112729 -
Chemical Society Reviews Jul 2022Protein phosphorylation is a crucial regulator of protein and cellular function, yet, despite identifying an enormous number of phosphorylation sites, the role of most... (Review)
Review
Protein phosphorylation is a crucial regulator of protein and cellular function, yet, despite identifying an enormous number of phosphorylation sites, the role of most is still unclear. Each phosphoform, the particular combination of phosphorylations, of a protein has distinct and diverse biological consequences. Aberrant phosphorylation is implicated in the development of many diseases. To investigate their function, access to defined protein phosphoforms is essential. Materials obtained from cells often are complex mixtures. Recombinant methods can provide access to defined phosphoforms if site-specifically acting kinases are known, but the methods fail to provide homogenous material when several amino acid side chains compete for phosphorylation. Chemical and chemoenzymatic synthesis has provided an invaluable toolbox to enable access to previously unreachable phosphoforms of proteins. In this review, we selected important tools that enable access to homogeneously phosphorylated protein and discuss examples that demonstrate how they can be applied. Firstly, we discuss the synthesis of phosphopeptides and proteins through chemical and enzymatic means and their advantages and limitations. Secondly, we showcase illustrative examples that applied these tools to answer biological questions pertaining to proteins involved in signal transduction, control of transcription, neurodegenerative diseases and aggregation, apoptosis and autophagy, and transmembrane proteins. We discuss the opportunities and challenges in the field.
Topics: Biology; Phosphopeptides; Phosphorylation; Proteins; Signal Transduction
PubMed: 35726784
DOI: 10.1039/d1cs00991e -
International Journal of Molecular... Jun 2022Protein phosphorylation is the most frequent post-translational modification (PTM) that plays important regulatory roles in a wide range of biological processes.... (Review)
Review
Protein phosphorylation is the most frequent post-translational modification (PTM) that plays important regulatory roles in a wide range of biological processes. Phosphorylation mainly occurs on serine (Ser), threonine (Thr), and tyrosine (Tyr) residues, with the phosphorylated Tyr sites accounting for ~1-2% of all phosphorylated residues. Tyr phosphorylation was initially believed to be less common in plants compared to animals; however, recent investigation indicates otherwise. Although they lack typical protein Tyr kinases, plants possess many dual-specificity protein kinases that were implicated in diverse cellular processes by phosphorylating Ser, Thr, and Tyr residues. Analyses of sequenced plant genomes also identified protein Tyr phosphatases and dual-specificity protein phosphatases. Recent studies have revealed important regulatory roles of Tyr phosphorylation in many different aspects of plant growth and development and plant interactions with the environment. This short review summarizes studies that implicated the Tyr phosphorylation in biosynthesis and signaling of plant hormones.
Topics: Animals; Biological Phenomena; Hormones; Phosphorylation; Plant Development; Plant Growth Regulators; Plants; Protein Processing, Post-Translational; Serine; Threonine; Tyrosine
PubMed: 35743047
DOI: 10.3390/ijms23126603 -
Chemical Reviews Jun 2020The formation of organophosphate molecules by prebiotic processes relies on nonenzymatic synthesis. Given the centrality of phosphorylated biomolecules in metabolic,... (Review)
Review
The formation of organophosphate molecules by prebiotic processes relies on nonenzymatic synthesis. Given the centrality of phosphorylated biomolecules in metabolic, structural, and replicative processes, it is highly likely that such nonenzymatic synthesis had to occur early in Earth's history. This Review collects and uses thermodynamic data to constrain processes that may have produced organophosphates and evaluates both the plausibility of reactants and the likelihood that environments conducive to phosphorylation were present. The energy required to phosphorylate organics is ∼15 kJ/mol, requiring either very low water activities or reactive inorganic phosphorus compounds. Thermodynamics permits evaluating phosphorylation environments for both plausibility and novelty and shows that several routes would have been available to form these potentially key reagents. Building from phosphate monoesters to diesters may have enabled the synthesis of nucleic acids, perhaps opening a way into the RNA world.
Topics: Evolution, Chemical; Nucleic Acids; Organophosphates; Phosphorylation; Thermodynamics
PubMed: 31736304
DOI: 10.1021/acs.chemrev.9b00492 -
Frontiers in Immunology 2022The SARS-CoV-2 infection triggers host kinases and is responsible for heavy phosphorylation in the host and also in the virus. Notably, phosphorylations in virus were... (Review)
Review
The SARS-CoV-2 infection triggers host kinases and is responsible for heavy phosphorylation in the host and also in the virus. Notably, phosphorylations in virus were achieved using the host enzyme for its better survival and further mutations. We have attempted to study and understand the changes that happened in phosphorylation during and post SARS-CoV-2 infection. There were about 70 phosphorylation sites detected in SARS-CoV-2 viral proteins including N, M, S, 3a, and 9b. Furthermore, more than 15,000 host phosphorylation sites were observed in SARS-CoV-2-infected cells. SARS-CoV-2 affects several kinases including CMGC, CK2, CDK, PKC, PIKFYVE, and EIF2AK2. Furthermore, SARS-CoV-2 regulates various signaling pathways including MAPK, GFR signaling, TGF-β, autophagy, and AKT. These elevated kinases and signaling pathways can be potential therapeutic targets for anti-COVID-19 drug discovery. Specific inhibitors of these kinases and interconnected signaling proteins have great potential to cure COVID-19 patients and slow down the ongoing COVID-19 pandemic.
Topics: Antiviral Agents; Autophagy; Humans; Phosphorylation; Signal Transduction; COVID-19 Drug Treatment
PubMed: 35251015
DOI: 10.3389/fimmu.2022.829474 -
Journal of the American Chemical Society Aug 2020Small molecules have been classically developed to inhibit enzyme activity; however, new classes of small molecules that endow new functions to enzymes via...
Small molecules have been classically developed to inhibit enzyme activity; however, new classes of small molecules that endow new functions to enzymes via proximity-mediated effect are emerging. Phosphorylation (native or neo) of any given protein-of-interest can alter its structure and function, and we hypothesized that such modifications can be accomplished by small molecules that bring a kinase in proximity to the protein-of-interest. Herein, we describe phosphorylation-inducing chimeric small molecules (PHICS), which enable two example kinases-AMPK and PKC-to phosphorylate target proteins that are not otherwise substrates for these kinases. PHICS are formed by linking small-molecule binders of the kinase and the target protein, and exhibit several features of a bifunctional molecule, including the hook-effect, turnover, isoform specificity, dose and temporal control of phosphorylation, and activity dependent on proximity (i.e., linker length). Using PHICS, we were able to induce native and neo-phosphorylations of BRD4 by AMPK or PKC. Furthermore, PHICS induced a signaling-relevant phosphorylation of the target protein Bruton's tyrosine kinase in cells. We envision that PHICS-mediated native or neo-phosphorylations will find utility in basic research and medicine.
Topics: Molecular Structure; Phosphorylation; Small Molecule Libraries
PubMed: 32787262
DOI: 10.1021/jacs.0c05537 -
Biochemical Society Transactions Aug 2013Since the discovery of protein kinases, protein phosphorylation has emerged as a key regulatory mechanism. The majority of phosphoproteins reside within the nucleus and... (Review)
Review
Since the discovery of protein kinases, protein phosphorylation has emerged as a key regulatory mechanism. The majority of phosphoproteins reside within the nucleus and cytoplasm; however, many secreted proteins are phosphorylated by unknown kinases located within the secretory pathway and/or in the extracellular space. The Fam20 kinases are emerging as the enzymes responsible for phosphorylating secreted proteins and proteoglycans. Evolutionary analysis reveals that these kinases are exclusively present in metazoans and contain conserved features that are common among all eukaryotic protein kinases. Mutations in the Fam20 family members cause disorders of biomineralization in humans that highlight the physiological significance of secreted protein phosphorylation.
Topics: Amino Acid Sequence; Humans; Molecular Sequence Data; Phosphorylation; Protein Kinases; Sequence Homology, Amino Acid; Substrate Specificity
PubMed: 23863179
DOI: 10.1042/BST20130059 -
Microbiology (Reading, England) Sep 2015Reversible phosphorylation of bacterial transcriptional regulators (TRs) belonging to the family of two-component systems (TCSs) is a well-established mechanism for... (Review)
Review
Reversible phosphorylation of bacterial transcriptional regulators (TRs) belonging to the family of two-component systems (TCSs) is a well-established mechanism for regulating gene expression. Recent evidence points to the fact that reversible phosphorylation of bacterial TRs on other types of residue, i.e. serine, threonine, tyrosine and cysteine, is also quite common. The phosphorylation of the ester type (phospho-serine/threonine/tyrosine) is more stable than the aspartate phosphorylation of TCSs. The kinases which catalyse these phosphorylation events (Hanks-type serine/threonine protein kinases and bacterial protein tyrosine kinases) are also much more promiscuous than the TCS kinases, i.e. each of them can phosphorylate several substrate proteins. As a consequence, the dynamics and topology of the signal transduction networks depending on these kinases differ significantly from the TCSs. Here, we present an overview of different classes of bacterial TR phosphorylated and regulated by serine/threonine and tyrosine kinases. Particular attention is given to examples when serine/threonine and tyrosine kinases interact with TCSs, phosphorylating either the histidine kinases or the response regulators. We argue that these promiscuous kinases connect several signal transduction pathways and serve the role of signal integration.
Topics: Bacterial Proteins; Gene Expression Regulation, Bacterial; Histidine Kinase; Phosphorylation; Protein Kinases; Protein Serine-Threonine Kinases; Serine; Signal Transduction; Threonine; Transcription Factors; Tyrosine
PubMed: 26220449
DOI: 10.1099/mic.0.000148 -
Bioorganic & Medicinal Chemistry Aug 2016Protein-protein interaction is one of the key events in the signal transduction pathway. The interaction changes the conformations, activities, localization and... (Review)
Review
Protein-protein interaction is one of the key events in the signal transduction pathway. The interaction changes the conformations, activities, localization and stabilities of the proteins, and transduces the signal to the next step. Frequently, this interaction occurs upon the protein phosphorylation. When upstream signals are stimulated, protein kinase(s) is/are activated and phosphorylate(s) their substrates, and induce the phosphorylation dependent protein-protein interaction. For this interaction, several domains in proteins are known to specifically recognize the phosphorylated residues of target proteins. These specific domains for interaction are important in the progression of the diseases caused by disordered signal transduction such as cancer. Thus small molecules that modulate this interaction are attractive lead compounds for the treatment of such diseases. In this review, we focused on three examples of phosphorylation dependent protein-protein interaction modules (14-3-3, polo box domain of Plk1 and F-box proteins in SCF ubiquitin ligases) and summarize small molecules that modulate their interaction. We also introduce our original screening system to identify such small molecules.
Topics: Animals; Cell Cycle Proteins; Humans; Phosphorylation; Protein Binding; Protein Interaction Maps; Signal Transduction; Small Molecule Libraries
PubMed: 27017542
DOI: 10.1016/j.bmc.2016.03.023