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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 -
Nature Cell Biology May 2023Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth...
Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.
Topics: Animals; Humans; Mice; Carcinoma, Hepatocellular; Creatine Kinase; Ferroptosis; Liver Neoplasms; Phosphorylation
PubMed: 37156912
DOI: 10.1038/s41556-023-01133-9 -
Biological & Pharmaceutical Bulletin Jul 2018AMP-activated protein kinase (AMPK) is a metabolic sensor in mammals that is activated when ATP levels in the cell decrease. AMPK is a heterotrimeric protein that... (Review)
Review
AMP-activated protein kinase (AMPK) is a metabolic sensor in mammals that is activated when ATP levels in the cell decrease. AMPK is a heterotrimeric protein that comprises 3 subunits, each of which has multiple phosphorylation sites that play critical roles in the regulation of either anabolism or catabolism by directly phosphorylating proteins or modulating gene transcription in multiple pathways, such as synthesis, oxidation and lipolysis of lipid. Research focused on the phosphorylation sites that are involved in lipid metabolism will lead to a better recognition of the role of AMPK in therapeutics for several common diseases. In this review, close attention is paid to the recent research on the structure, and multisite phosphorylation of AMPK subunits, as well as AMPK regulation of lipid metabolism via phosphorylation of related molecules.
Topics: AMP-Activated Protein Kinases; Adipose Tissue; Animals; Energy Metabolism; Humans; Lipid Metabolism; Liver; Phosphorylation; Protein Multimerization; Protein Subunits
PubMed: 29709897
DOI: 10.1248/bpb.b17-00724 -
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 -
Nature Plants Apr 2023Phosphorylation modification is required for the modulation of phytochrome B (phyB) thermal reversion, but the kinase(s) that phosphorylate(s) phyB and the biological...
Phosphorylation modification is required for the modulation of phytochrome B (phyB) thermal reversion, but the kinase(s) that phosphorylate(s) phyB and the biological significance of the phosphorylation are still unknown. Here we report that FERONIA (FER) phosphorylates phyB to regulate plant growth and salt tolerance, and the phosphorylation not only regulates dark-triggered photobody dissociation but also modulates phyB protein abundance in the nucleus. Further analysis indicates that phosphorylation of phyB by FER is sufficient to accelerate the conversion of phyB from the active form (Pfr) to the inactive form (Pr). Under salt stress, FER kinase activity is inhibited, leading to delayed photobody dissociation and increased phyB protein abundance in the nucleus. Our data also show that phyB mutation or overexpression of PIF5 attenuates growth inhibition and promotes plant survival under salt stress. Together, our study not only reveals a kinase that controls phyB turnover via a signature of phosphorylation, but also provides mechanistic insights into the role of the FER-phyB module in coordinating plant growth and stress tolerance.
Topics: Phytochrome B; Arabidopsis; Arabidopsis Proteins; Phosphorylation; Salt Tolerance; Plants; Light; Gene Expression Regulation, Plant
PubMed: 37012430
DOI: 10.1038/s41477-023-01390-4 -
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 -
Advances in Neurobiology 2017Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene were discovered in 2004 and have been found to be the most frequently mutated gene in Parkinson's disease.... (Review)
Review
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene were discovered in 2004 and have been found to be the most frequently mutated gene in Parkinson's disease. LRRK2 is a large multi-domain protein with a functional GTPase and kinase domain. The signal transduction pathways in which LRRK2 is dysfunctional in the disease state are only now being resolved, but we do know that LRRK2 is, itself, a substrate of multiple kinases and phosphatases and exists in variable phosphorylated states. Autophosphorylation of LRRK2 can impact GTPase and pathological outcomes. LRRK2 serines (910/935/955/973) are differentially phosphorylated in pathogenic PD mutations and after LRRK2 kinase inhibition. The phosphorylation status of LRRK2 can therefore provide key insight into the mechanisms of kinase dysfunction during disease. This chapter will describe the identification of LRRK2 phosphorylation sites and how phosphoregulation of LRRK2 reveals its own kinase activity and regulates its ubiquitination and localization in vitro, in cells, and in tissues.
Topics: Animals; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Parkinson Disease; Phosphorylation
PubMed: 28353278
DOI: 10.1007/978-3-319-49969-7_3 -
Molecular Cell Jun 2022Protein phosphorylation is a reversible post-translational modification. Nine of the 20 natural amino acids in proteins can be phosphorylated, but most of what we know... (Review)
Review
Protein phosphorylation is a reversible post-translational modification. Nine of the 20 natural amino acids in proteins can be phosphorylated, but most of what we know about the roles of protein phosphorylation has come from studies of serine, threonine, and tyrosine phosphorylation. Much less is understood about the phosphorylation of histidine, lysine, arginine, cysteine, aspartate, and glutamate, so-called non-canonical phosphorylations. Phosphohistidine (pHis) was discovered 60 years ago as a mitochondrial enzyme intermediate; since then, evidence for the existence of histidine kinases and phosphohistidine phosphatases has emerged, together with examples where protein function is regulated by reversible histidine phosphorylation. pHis is chemically unstable and has thus been challenging to study. However, the recent development of tools for studying pHis has accelerated our understanding of the multifaceted functions of histidine phosphorylation, revealing a large number of proteins that are phosphorylated on histidine and implicating pHis in a wide range of cellular processes.
Topics: Histidine; Phosphorylation; Phosphotyrosine; Proteins
PubMed: 35654043
DOI: 10.1016/j.molcel.2022.05.007 -
Advances in Neurobiology 2017LRRK2 is a highly phosphorylated protein, and evidence of a physiological role for LRRK2 phosphorylation has accumulated in recent years for cellular phosphosites, many... (Review)
Review
LRRK2 is a highly phosphorylated protein, and evidence of a physiological role for LRRK2 phosphorylation has accumulated in recent years for cellular phosphosites, many of which are found in the ANK-LRR interdomain region, i.e., the S910/S935/S955/S973 sites as well as recently for autophosphorylation sites, at least one of which has been confirmed in cells, S1292. LRRK2 phosphorylation is modulated in several disease or potential therapy relevant conditions such as in disease mutant variants of LRRK2 or following LRRK2 kinase inhibitor treatment. This chapter will focus on the regulation of LRRK2 phosphorylation and more specifically the role of phosphatases in LRRK2 dephosphorylation. This will include reviewing the conditions in which LRRK2 is found to be dephosphorylated, the molecular partners and phosphatases involved in regulating LRRK2 phosphorylation, as well as discussing how LRRK2 phosphatases may be therapeutic targets or biomarkers in their own right.
Topics: Animals; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Phosphoric Monoester Hydrolases; Phosphorylation
PubMed: 28353283
DOI: 10.1007/978-3-319-49969-7_8 -
Advances in Experimental Medicine and... 2019Protein modification refers to the chemical modification of proteins after their biosynthesis, which is also called posttranslational modification (PTM). PTM causes... (Review)
Review
Protein modification refers to the chemical modification of proteins after their biosynthesis, which is also called posttranslational modification (PTM). PTM causes changes in protein properties and functions. PTM includes an attachment of addition of functional groups, such as methylation, acetylation, glycosylation and phosphorylation; a covalent coupling of small peptides or proteins, such as ubiquitination and SUMOylation; or chemical changes in amino acids, such as citrullination (conversion of arginine to citrulline). Protein modification plays an important role in cellular processes. Since a protein can be modified in different ways, such as acetylation, methylation and phosphorylation, the functions of proteins are different under different modification states. Moreover, the same modification at different sites may have completely different effects on protein function. For example, phosphorylation at some sites in a protein may lead to a functional activation, while phosphorylation at other sites may cause an inhibition of the functions. Thus, different modifications, combinations and sites changes lead to different functional regulations of a protein, resulting in different effects in the cells. In autophagy, PTMs are widely involved in the regulation of autophagy, including ubiquitination, phosphorylation and acetylation. Ubiquitination is the covalent conjugation of ubiquitin to the substrates through a series of enzymes. Phosphorylation refers to an attachment of a phosphoryl group into a protein, primarily on serine, threonine and tyrosine, which is catalyzed by the kinases. Phosphorylation, a common modification, regulates protein function and localization. Phosphorylation in autophagy regulates the activity of autophagy-associated proteins and the initiation and progression of autophagy by regulating signaling pathways. Acetylation means the addition of acetyl groups onto lysine or N-terminal segment of target proteins through acetyltransferases. Acetylation and deacetylation are both involved in the regulation of autophagy initiation and selective autophagy by controlling the acetylation level of important proteins in the autophagy process. In this chapter, we will focus on the regulation of ubiquitination and phosphorylation in autophagy.
Topics: Acetylation; Autophagy; Phosphorylation; Protein Processing, Post-Translational; Sumoylation; Ubiquitination
PubMed: 31776989
DOI: 10.1007/978-981-15-0602-4_12