• Humans
• 14-3-3 Proteins/metabolism
• Insulin-Secreting Cells/metabolism
• Diabetes Mellitus/metabolism
• Homeostasis
• Glucose/metabolism
• Insulin/metabolism

• R56 DK124853 NIDDK NIH HHS
• Canadian Institutes of Health Research
• Hartwell Foundation
• Department of Defense
• NIH/NIDDK
• Canada Research Chairs
• NSERC

• MYC
• RAS
• RB
• onco-suppressors
• oncogenes
• p53
• post-translational modifications
• ubiquitin and ubiquitin-like proteins

• Humans
• Protein Processing, Post-Translational
• Ubiquitination
• Ubiquitin/metabolism
• Proteins/metabolism
• Homeostasis

• 2022 Fondazione Ricerca Oncologica Menesini (FROM)
• 2021 Associazione Umbra Contro il Cancro

• Malonic acid
• Nox1
• ROS
• Tolfenamic acid
• p53

• Animals
• Apoptosis
• Huntington Disease/genetics
• Huntington Disease/pathology
• Malonates
• Mice
• Oxidoreductases/metabolism
• Oxidoreductases/pharmacology
• RNA, Messenger
• Rats
• Reactive Oxygen Species/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Protein p53/pharmacology

• 81703494 Natural Science Foundation of China
• LJKZ0914 Science Foundation of the Educational Department of Liaoning Province
• ZQN2021004 Career Development Program for Young Teachers of Shenyang Pharmaceutical University

• aggregates
• amyloid
• oncogene
• p53
• structural biology
• tumor suppressor

• Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
• Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem

Reversible cysteine oxidation plays an essential role in redox signaling by reversibly altering protein structure and function. Cysteine oxidation may lead to intra- and intermolecular disulfide formation, and the latter can drastically stabilize protein–protein interactions in a more oxidizing milieu. The activity of the tumor suppressor p53 is regulated at multiple levels, including various post-translational modification (PTM) and protein–protein interactions. In the past few decades, p53 has been shown to be a redox-sensitive protein, and undergoes reversible cysteine oxidation both in vitro and in vivo. It is not clear, however, whether p53 also forms intermolecular disulfides with interacting proteins and whether these redox-dependent interactions contribute to the regulation of p53. In the present study, by combining (co-)immunoprecipitation, quantitative mass spectrometry and Western blot we found that p53 forms disulfide-dependent interactions with several proteins under oxidizing conditions. Cysteine 277 is required for most of the disulfide-dependent interactions of p53, including those with 14-3-3θ and 53BP1. These interaction partners may play a role in fine-tuning p53 activity under oxidizing conditions.

• cysteine oxidation
• disulfide
• p53
• protein–protein interaction

The genome guardian p53 functions as a transcription factor that senses numerous cellular stresses and orchestrates the corresponding transcriptional events involved in determining various cellular outcomes, including cell cycle arrest, apoptosis, senescence, DNA repair, and metabolic regulation. In response to diverse stresses, p53 undergoes multiple posttranslational modifications (PTMs) that coordinate with intimate interdependencies to precisely modulate its diverse properties in given biological contexts. Notably, PTMs can recruit ‘reader’ proteins that exclusively recognize specific modifications and facilitate the functional readout of p53. Targeting PTM–reader interplay has been developing into a promising cancer therapeutic strategy. In this review, we summarize the advances in deciphering the ‘PTM codes’ of p53, focusing particularly on the mechanisms by which the specific reader proteins functionally decipher the information harbored within these PTMs of p53. We also highlight the potential applications of intervention with p53 PTM–reader interactions in cancer therapy and discuss perspectives on the ‘PTMomic’ study of p53 and other proteins.

• PTM code
• p53
• posttranslational modification
• reader
• tumor therapy

• 14-3-3
• 14-3-3-p53 protein-protein interaction stabilization
• MDM2-p53 protein-protein interaction inhibition
• p53

• Humans
• Protein Binding/physiology
• Tumor Suppressor Protein p53/metabolism

• P53 pathway
• cancers
• embryonic and somatic cells
• mutations

• Animals
• Carcinogenesis/genetics
• Carcinogenesis/pathology
• Germ Cells/pathology
• Humans
• Neoplasms/genetics
• Neoplasms/pathology
• Signal Transduction/genetics
• Tumor Suppressor Protein p53/genetics

• tumour-suppressor proteins

• cancer
• gene expression
• gene regulation
• p53
• tumour suppressor

• 14-3-3 protein
• AKT
• Bad
• Curcumin
• apoptosis

TP53 is the most frequently mutated gene across all cancer types. Our understanding of its functions has evolved since its discovery four decades ago. Initially thought to be an oncogene, it was later realized to be a critical tumour suppressor. A significant amount of our knowledge about p53 functions have come from the use of antibodies against its various forms. The early anti-p53 antibodies contributed to the recognition of p53 accumulation as a common feature of cancer cells and to our understanding of p53 DNA-binding and transcription activities. They led to the concept that conformational changes can facilitate p53’s activity as a growth inhibitory protein. The ensuing p53 conformational-specific antibodies further underlined p53’s conformational flexibility, collectively forming the basis for current efforts to generate therapeutic molecules capable of altering the conformation of mutant p53. A subsequent barrage of antibodies against post-translational modifications on p53 has clarified p53’s roles further, especially with respect to the mechanistic details and context-dependence of its activity. More recently, the generation of p53 mutation-specific antibodies have highlighted the possibility to go beyond the general framework of our comprehension of mutant p53—and promises to provide insights into the specific properties of individual p53 mutants. This review summarizes our current knowledge of p53 functions derived through the major classes of anti-p53 antibodies, which could be a paradigm for understanding other molecular events in health and disease.

• antibodies
• conformation
• mutant
• p53
• post-translational modifications

• acetylation
• deacetylation
• methylation
• p53
• phosphorylation
• transcriptional regulation
• ubiquitination

• Animals
• History, 20th Century
• History, 21st Century
• Humans
• Neoplasms/genetics
• Neoplasms/history
• Neoplasms/metabolism
• Neoplasms/pathology
• Protein Processing, Post-Translational
• Protein Stability
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/history
• Tumor Suppressor Protein p53/metabolism

• R01 CA190477 NCI NIH HHS
• R01 CA224272 NCI NIH HHS
• R01 CA216884 NCI NIH HHS
• R01 CA085533 NCI NIH HHS
• R01 CA193890 NCI NIH HHS

• 14-3-3
• BRCT
• Binding domain
• FHA
• Phosphopeptide
• WD40

• 14-3-3 Proteins/metabolism
• Animals
• Humans
• Signal Transduction/physiology
• Stress, Physiological/physiology

• R01 GM117400 NIGMS NIH HHS
• R15 CA202618 NCI NIH HHS

The protein containing the C2 domain has been well documented for its essential roles in endocytosis, cellular metabolism and cancer. Tac2-N (TC2N) is a tandem C2 domain-containing protein, but its function, including its role in tumorigenesis, remains unknown. Here, we first identified TC2N as a novel oncogene in lung cancer. TC2N was preferentially upregulated in lung cancer tissues compared with adjacent normal lung tissues. High TC2N expression was significantly associated with poor outcome of lung cancer patients. Knockdown of TC2N markedly induces cell apoptosis and cell cycle arrest with repressing proliferation in vitro, and suppresses tumorigenicity in vivo, whereas overexpression of TC2N has the opposite effects both in vitro and in vivo. Using a combination of TCGA database and bioinformatics, we demonstrate that TC2N is involved in regulation of the p53 signaling pathway. Mechanistically, TC2N attenuates p53 signaling pathway through inhibiting Cdk5-induced phosphorylation of p53 via inducing Cdk5 degradation or disrupting the interaction between Cdk5 and p53. Moreover, the blockade of p53 attenuates the function of TC2N knockdown in the regulation of cell proliferation and apoptosis. In addition, downregulated TC2N is involved in the apoptosis of lung cancer cells induced by doxorubicin, leading to p53 pathway activation. Overall, these findings uncover a role for the p53 inactivator TC2N in regulating the proliferation and apoptosis of lung cancer cells. Our present study provides novel insights into the mechanism of tumorigenesis in lung cancer.

• Chk1/Chk2
• DNA damage
• E6
• HPV
• PBM
• p53

Recent studies showed that induced microRNA-449a (miR-449a) enhances a G2/M cell cycle checkpoint arrest in prostate cancer (LNCaP) and lung adenocarcinoma cell lines. In the case of LNCaP cells, upregulated miR-449a directly downregulates c-Myc that is required to induce the cell cycle regulators Cdc25A and Cdc2/CyclinB whose inactivation blocks G2 to M phase transition. However, the molecular mechanisms involved are yet unclear, although in other prostate cancer cells the interactions among p53, miR-449a and Sirt-1 can affect the induction of the G2/M arrest. In order to clarify these molecular mechanisms, in this work we propose a boolean model of the G2/M checkpoint arrest regulation contemplating the influence of miR-449a. The model shows that the cell fate determination between two cellular phenotypes: G2/M-Arrest for DNA repair and G2/M-induced apoptosis is stochastic and influenced by miR-449a state of activation. The results were compared with experimental data available presenting agreement. We also found that several feedback loops are involved in this cell fate regulation and we indicate, through in silico gain or loss of function perturbations of genes, which of these feedback loops are more efficient to favor a specific phenotype.

• Apoptosis/radiation effects
• Cell Line, Tumor
• Cell Proliferation/radiation effects
• G2 Phase Cell Cycle Checkpoints/radiation effects
• Gene Expression Regulation, Neoplastic/genetics
• Gene Expression Regulation, Neoplastic/radiation effects
• Humans
• Male
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Prostatic Neoplasms/genetics
• Radiation, Ionizing

• Conselho Nacional de Desenvolvimento Científico e Tecnológico
• Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Maternal control of development begins with production of the oocyte during oogenesis. All of the factors necessary to complete oocyte maturation, meiosis, fertilization, and early development are produced in the transcriptionally active early oocyte. Active transcription of the maternal genome is a mechanism to ensure that the oocyte and development of the early embryo begin with all of the factors needed for successful embryonic development. To achieve the maximum maternal store, only one functional cell is produced from the meiotic divisions that produce the oocyte. The oocyte receives the bulk of the maternal cytoplasm and thus is significantly larger than its sister cells, the tiny polar bodies, which receive a copy of the maternal genome but essentially none of the maternal cytoplasm. This asymmetric division is accomplished by an enormous cell that is depleted of centrosomes in early oogenesis; thus, meiotic divisions in oocytes are distinct from those of mitotic cells. Therefore, these cells must partition the chromosomes faithfully to ensure euploidy by using mechanisms that do not rely on a conventional centrosome-based mitotic spindle. Several mechanisms that contribute to assembly and maintenance of the meiotic spindle in oocytes have been identified; however, none is fully understood. In recent years, there have been many exciting and significant advances in oogenesis, contributed by studies using a myriad of systems. Regrettably, I cannot adequately cover all of the important advances here and so I apologize to those whose beautiful work has not been included. This review focuses on a few of the most recent studies, conducted by several groups, using invertebrate and vertebrate systems, that have provided mechanistic insight into how microtubule assembly and meiotic spindle morphogenesis are controlled in the absence of centrosomes.

• actin
• meiosis
• microtubules
• oocyte
• oogenesis

• 15N detection
• IDP
• NFAT
• NMR resonance assignment
• nuclear localization

• 14-3-3 proteins
• cancer
• cell cycle
• cell proliferation
• lung cancer
• protein interaction

Early studies indicated that mast cells in prostate tumor microenvironment might influence prostate cancer (PCa) progression. Their impacts to PCa therapy, however, remained unclear. Here we found PCa could recruit more mast cells than normal prostate epithelial cells then alter PCa chemotherapy and radiotherapy sensitivity, leading to PCa more resistant to these therapies. Mechanism dissection revealed that infiltrated mast cells could increase p21 expression via modulation of p38/p53 signals, and interrupting p38-p53 signals via siRNAs of p53 or p21 could reverse mast cell-induced docetaxel chemotherapy resistance of PCa. Furthermore, recruited mast cells could also increase the phosphorylation of ATM at ser-1981 site, and inhibition of ATM activity could reverse mast cell-induced radiotherapy resistance. The in vivo mouse model with xenografted PCa C4-2 cells co-cultured with mast cells also confirmed that mast cells could increase PCa chemotherapy resistance via activating p38/p53/p21 signaling. Together, our results provide a new mechanism showing infiltrated mast cells could alter PCa chemotherapy and radiotherapy sensitivity via modulating the p38/p53/p21 signaling and phosphorylation of ATM. Targeting this newly identified signaling may help us better suppress PCa chemotherapy and radiotherapy resistance.

• ATM
• docetaxel
• p38
• prostate cancer
• radiotherapy

• 14-3-3; Aedes aegypti
• RNA
• expression
• proteins

• 14-3-3 Proteins/chemistry
• 14-3-3 Proteins/genetics
• 14-3-3 Proteins/metabolism
• Aedes/classification
• Aedes/genetics
• Aedes/growth & development
• Aedes/metabolism
• Amino Acid Sequence
• Animals
• Female
• Gene Expression Regulation, Developmental
• Insect Proteins/chemistry
• Insect Proteins/genetics
• Insect Proteins/metabolism
• Insect Vectors/genetics
• Insect Vectors/metabolism
• Larva/genetics
• Larva/growth & development
• Larva/metabolism
• Male
• Organ Specificity
• Phylogeny
• Polymerase Chain Reaction
• Pupa/genetics
• Pupa/growth & development
• Pupa/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Sequence Alignment

The in vivo requirement of the histone demethylase JmjD2A, together with the kinase MSK1, results in a series of epigenetic events necessary for early activation of Sox2 and subsequent neural fate commitment in vertebrates.

One of the earliest manifestations of neural induction is onset of expression of the neural marker Sox2, mediated by the activation of the enhancers N1 and N2. By using loss and gain of function, we find that Sox2 expression requires the activity of JmjD2A and the Msk1 kinase, which can respectively demethylate the repressive H3K9me3 mark and phosphorylate the activating H3S10 (H3S10ph) mark. Bimolecular fluorescence complementation reveals that the adaptor protein 14-3-3, known to bind to H3S10ph, interacts with JMJD2A and may be involved in its recruitment to regulatory regions of the Sox2 gene. Chromatin immunoprecipitation reveals dynamic binding of JMJD2A to the Sox2 promoter and N-1 enhancer at the time of neural plate induction. Finally, we show a clear temporal antagonism on the occupancy of H3K9me3 and H3S10ph modifications at the promoter of the Sox2 locus before and after the neural plate induction. Taken together, our results propose a series of epigenetic events necessary for the early activation of the Sox2 gene in neural progenitor cells.

• 14-3-3 zeta
• Cell biology
• Cytoskeleton
• Head and neck cancer
• Metastasis
• Protein networks

• ATM
• DNA damage
• Mdm2
• SMG7
• cell cycle arrest
• p53
• phosphorylation
• transcription factor

• R01 GM112085 NIGMS NIH HHS

• MDM2
• p53
• post-translational modification
• signalling
• tumour suppressor

Phosphorylation at the C-terminal flexible region of the C-Raf protein plays an important role in regulating its biological activity. Auto-phosphorylation at serine 621 (S621) in this region maintains C-Raf stability and activity. This phosphorylation mediates the interaction between C-Raf and scaffold protein 14-3-3ζ to activate the downstream MEK kinase pathway. In this study, we have defined the interaction of C-terminal peptide sequence of C-Raf with 14-3-3ζ protein and determined the possible structural adaptation of this region. Biophysical elucidation of the interaction was carried out using phosphopeptide (residue number 615–630) in the presence of 14-3-3ζ protein. Using isothermal titration calorimetry (ITC), a high binding affinity with micro-molar range was found to exist between the peptide and 14-3-3ζ protein, whereas the non-phosphorylated peptide did not show any appreciable binding affinity. Further interaction details were investigated using several biophysical techniques such as circular dichroism (CD), fluorescence, and nuclear magnetic resonance (NMR) spectroscopy, in addition to molecular modeling. This study provides the molecular basis for C-Raf C-terminal-derived phosphopeptide interaction with 14-3-3ζ protein as well as structural insights responsible for phosphorylated S621-mediated 14-3-3ζ binding at an atomic resolution.

• 14-3-3 Proteins/chemistry
• 14-3-3 Proteins/genetics
• Amino Acid Sequence
• Binding Sites
• Cloning, Molecular
• Escherichia coli/genetics
• Escherichia coli/metabolism
• Gene Expression
• Humans
• Kinetics
• Molecular Docking Simulation
• Molecular Sequence Data
• Peptides/chemical synthesis
• Peptides/chemistry
• Phosphorylation
• Pliability
• Protein Binding
• Protein Structure, Secondary
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-raf/chemistry
• Proto-Oncogene Proteins c-raf/genetics
• Recombinant Proteins/chemistry
• Recombinant Proteins/genetics
• Thermodynamics

The p53 protein is a master regulator of the stress response. It acts as a tumor suppressor by inducing transcriptional activation of p53 target genes, with roles in apoptosis, cell cycle arrest and metabolism. The discovery of at least 12 isoforms of p53, some of which have tumor-promoting properties, has opened new avenues of research. Our previous work studied tumor phenotypes in four mouse models with different p53 backgrounds: wild-type p53, p53 null, mutant p53 lacking the proline domain (mΔpro), and a mimic for the human Δ133p53α p53 isoform (Δ122p53). To identify the major proteins affected by p53 function early in the response to DNA damage, the current study investigated the entire proteome of bone marrow, thymus, and lung in the four p53 models. Protein extracts from untreated controls and those treated with amsacrine were analyzed using two-dimensional fluorescence difference gel electrophoresis. In the bone marrow, reactive proteins were universally decreased by wild-type p53, including α-enolase. Further analysis of α-enolase in the p53 models revealed that it was instead increased in Δ122p53 hematopoietic and tumor cell cytosol and on the cell surface. Alpha-enolase on the surface of Δ122p53 cells acted as a plasminogen receptor, with tumor necrosis factor alpha induced upon plasminogen stimulation. Taken together, these data identified new proteins associated with p53 function. One of these proteins, α-enolase, is regulated differently by wild-type p53 and Δ122p53 cells, with reduced abundance as part of a wild-type p53 response and increased abundance with Δ122p53 function. Increased cell surface α-enolase on Δ122p53 cells provides a possible explanation for the model’s pro-inflammatory features and suggests that p53 isoforms may direct an inflammatory response by increasing the amount of α-enolase on the cell surface.

• Animals
• Cell Line, Tumor
• Cell Membrane/metabolism
• Enzyme Activation
• Gene Expression Regulation
• Humans
• Leukocytes, Mononuclear/cytology
• Male
• Mice
• Mutation
• NF-kappa B/metabolism
• Organ Specificity
• Phosphopyruvate Hydratase/metabolism
• Plasminogen/metabolism
• Protein Isoforms/genetics
• Proteomics
• Signal Transduction
• Tumor Suppressor Protein p53/genetics
• Ubiquitin C/metabolism
• Up-Regulation

• Molecular dynamics simulation
• Mutation
• Small molecule inhibitor
• Thermodynamic
• p53

• cancer
• genotoxic stress
• miRNA
• p53
• post-translational modifications

This review opens a new series entitled “Unreported intrinsic disorder in proteins.” The goal of this series is to bring attention of researchers to an interesting phenomenon of missed (or overlooked, or ignored, or unreported) disorder. This series serves as a companion to “Digested Disorder” which provides a quarterly review of papers on intrinsically disordered proteins (IDPs) found by standard literature searches. The need for this alternative series results from the observation that there are numerous publications that describe IDPs (or hybrid proteins with ordered and disordered regions) yet fail to recognize many of the key discoveries and publications in the IDP field. By ignoring the body of work on IDPs, such publications often fail to relate their findings to prior discoveries or fail to explore the obvious implications of their work. Thus, the goal of this series is not only to review these very interesting and important papers, but also to point out how each paper relates to the IDP field and show how common tools in the IDP field can readily take the findings in new directions or provide a broader context for the reported findings.

• intrinsically disordered protein
• molecular recognition
• posttranslational modification
• protein function
• protein-protein interaction

• Cell organization
• Cell signaling
• Cell structure
• Diffusion
• Signal transduction
• Signaling modules

• 14-3-3 Proteins/metabolism
• Animals
• Cells/cytology
• Cells/metabolism
• Humans
• Membrane Microdomains/metabolism
• Signal Transduction
• ras GTPase-Activating Proteins/metabolism

• HHSN261200800001C NCI NIH HHS
• HHSN261200800001E NCI NIH HHS
• Z01 BC010441-06 Intramural NIH HHS

• Adaptor Protein
• Mitochondria
• Post-translational Modification (PTM)
• Steroidogenesis
• Testis

• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Brain/metabolism
• Brain/pathology
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Cluster Analysis
• Electrophoresis, Gel, Two-Dimensional
• Glioma/metabolism
• Glioma/pathology
• Humans
• Immunohistochemistry
• Mass Spectrometry
• Multivariate Analysis
• Protein Interaction Maps
• Proteome/analysis
• Proteome/metabolism
• Proteomics/methods
• Signal Transduction

• DNA damage repair
• cell cycle control
• diabetes
• germ cell apoptosis
• testicular dysfunction

• 8-Hydroxy-2'-Deoxyguanosine
• Animals
• Apoptosis
• Cell Cycle
• Cyclin-Dependent Kinase Inhibitor p21/metabolism
• DNA Damage
• DNA, Mitochondrial/metabolism
• Deoxyguanosine/analogs & derivatives
• Deoxyguanosine/metabolism
• Diabetes Mellitus, Experimental/metabolism
• Diabetes Mellitus, Experimental/pathology
• Male
• Oxidative Stress
• Phosphorylation
• Rats, Sprague-Dawley
• Signal Transduction
• Spermatozoa/metabolism
• Spermatozoa/pathology
• Testis/metabolism
• Testis/pathology
• Time Factors
• Tumor Suppressor Protein p53/metabolism

Systematic analysis of histone modifications has revealed a plethora of posttranslational modifications that mediate changes in chromatin structure and gene expression. Histone phosphorylation is a transient histone modification that becomes induced by extracellular signals, DNA damage or entry into mitosis. Importantly, phosphorylation of histone proteins does lead not only to the binding of specific reader proteins but also to changes in the affinity for readers or writers of other histone modifications. This induces a cross-talk between different chromatin modifications that allows the spatio-temporal control of chromatin-associated events. In this review we will summarize the progress in our current knowledge of factors sensing reversible histone phosphorylation in different biological scenarios. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.

•

Signal induced histone phosphorylation is associated with local chromatin opening and transcriptional activation.

• DNA damage
• Histone code
• Histone phosphorylation
• Mitosis
• Transcription

• 14-3-3 Proteins/genetics
• 14-3-3 Proteins/metabolism
• Acetylation
• Chromatin/chemistry
• Chromatin/genetics
• Chromatin/metabolism
• DNA Damage
• Epigenesis, Genetic
• Eukaryotic Cells/cytology
• Eukaryotic Cells/metabolism
• Histones/genetics
• Histones/metabolism
• Humans
• Methylation
• Mitosis
• Phosphorylation
• Protein Binding
• Protein Interaction Domains and Motifs
• Protein Processing, Post-Translational
• Signal Transduction
• Transcription, Genetic

The copy number of membrane proteins at the cell surface is tightly regulated. Many ion channels and receptors present retrieval motifs to COPI vesicle coats and are retained in the early secretory pathway. In some cases, the interaction with COPI is prevented by binding to 14-3-3 proteins. However, the functional significance of this antagonism between COPI and 14-3-3 in terminally differentiated cells is unknown. Here, we show that ATP-sensitive K⁺ (K_ATP) channels, which are composed of Kir6.2 and SUR1 subunits, are stalled in the Golgi complex of ventricular, but not atrial, cardiomyocytes. Upon sustained β-adrenergic stimulation, which leads to activation of protein kinase A (PKA), SUR1-containing channels reach the plasma membrane of ventricular cells. We show that PKA-dependent phosphorylation of the C-terminus of Kir6.2 decreases binding to COPI and, thereby, silences the arginine-based retrieval signal. Thus, activation of the sympathetic nervous system releases this population of K_ATP channels from storage in the Golgi and, hence, might facilitate the adaptive response to metabolic challenges.

• 14-3-3
• ATP-sensitive K+ channels
• Arg-based retrieval signal
• COPI
• Cardiomyocyte
• Coatomer
• KATP
• PKA
• Protein kinase A
• Trafficking

• TP53
• acetylation
• methylation
• p53
• phosphorylation
• transcription
• ubiquitylation

• Cell Death
• Nucleolus
• Post-translational Modification
• Stress Response
• p300
• p53

• 14-3-3 Proteins/metabolism
• Cell Line
• Cyclic AMP-Dependent Protein Kinases/metabolism
• Cyclic GMP-Dependent Protein Kinases/metabolism
• Humans
• Immunoprecipitation
• Phosphorylation
• RGS Proteins/metabolism
• Signal Transduction/physiology

• HSQC
• ITC
• NMR
• X-ray crystallography
• heteronuclear single quantum coherence
• integrin cytoplasmic domains
• isothermal titration calorimetry
• nuclear magnetic resonance
• protein–protein interactions
• wild type
• wt

• 14-3-3 Proteins/chemistry
• 14-3-3 Proteins/metabolism
• Crystallography, X-Ray
• Cytoplasm/metabolism
• Integrin alpha4/chemistry
• Integrin alpha4/metabolism
• Integrin beta Chains/chemistry
• Integrin beta Chains/metabolism
• Paxillin/metabolism
• Phosphorylation
• Protein Binding
• Protein Interaction Domains and Motifs
• Talin/chemistry
• Talin/metabolism

• 088497/Z/09/Z Wellcome Trust
• BB/J008265/1 Biotechnology and Biological Sciences Research Council
• 094872/Z/10/Z Wellcome Trust
• G09000521 Medical Research Council
• Wellcome Trust
• G0900052 Medical Research Council