-
Science Advances Jul 2022Exposure to cold triggers a spike in cytosolic calcium (Ca) that often leads to transcriptional reprogramming in plants. However, how this Ca signal is perceived and...
Exposure to cold triggers a spike in cytosolic calcium (Ca) that often leads to transcriptional reprogramming in plants. However, how this Ca signal is perceived and relayed to the downstream cold signaling pathway remains unknown. Here, we show that the CALCIUM-DEPENDENT PROTEIN KINASE 28 (CPK28) initiates a phosphorylation cascade to specify transcriptional reprogramming downstream of cold-induced Ca signal. Plasma membrane (PM)-localized CPK28 is activated rapidly upon cold shock within 10 seconds in a Ca-dependent manner. CPK28 then phosphorylates and promotes the nuclear translocation of NIN-LIKE PROTEIN 7 (NLP7), a transcription factor that specifies the transcriptional reprogramming of gene sets in response to Ca, thereby positively regulating plant response to cold stress. This study elucidates a previously unidentified mechanism by which the CPK28-NLP7 regulatory module integrates cold-evoked Ca signal and transcriptome and thus uncovers a key strategy for the rapid perception and transduction of cold signals from the PM to the nucleus.
Topics: Arabidopsis; Arabidopsis Proteins; Gene Expression Regulation, Plant; Protein Kinases
PubMed: 35767615
DOI: 10.1126/sciadv.abn7901 -
Cancer Gene Therapy Sep 2023Gastrointestinal cancers are a leading cause of cancer morbidity and mortality worldwide with 4.2 million new cases and 3.2 million deaths estimated in 2020. Despite the... (Review)
Review
Gastrointestinal cancers are a leading cause of cancer morbidity and mortality worldwide with 4.2 million new cases and 3.2 million deaths estimated in 2020. Despite the advances in primary and adjuvant therapies, patients still develop distant metastases and require novel therapies. Mitogen‑activated protein kinase (MAPK) cascades are crucial signaling pathways that regulate many cellular processes, including proliferation, differentiation, apoptosis, stress responses and cancer development. p38 Mitogen Activated Protein Kinases (p38 MAPKs) includes four isoforms: p38α (MAPK14), p38β (MAPK11), p38γ (MAPK12), and p38δ (MAPK13). p38 MAPK was first identified as a stress response protein kinase that phosphorylates different transcriptional factors. Dysregulation of p38 pathways, in particular p38γ, are associated with cancer development, metastasis, autophagy and tumor microenvironment. In this article, we provide an overview of p38 and p38γ with respect to gastrointestinal cancers. Furthermore, targeting p38γ is also discussed as a potential therapy for gastrointestinal cancers.
Topics: Humans; Mitogen-Activated Protein Kinase 11; Mitogen-Activated Protein Kinase 12; Mitogen-Activated Protein Kinase 13; Signal Transduction; Gastrointestinal Neoplasms; p38 Mitogen-Activated Protein Kinases; Tumor Microenvironment
PubMed: 37248432
DOI: 10.1038/s41417-023-00622-1 -
Nature Dec 2020The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology, and more recently in...
The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology, and more recently in immunotherapy and ageing. However, many MEK inhibitors are limited owing to on-target toxicities and drug resistance. Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEK inhibitors, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. In the bound complex, KSR remodels the prototypical allosteric pocket of the MEK inhibitor, thereby affecting binding and kinetics, including the drug-residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these sub-complexes. On the basis of these insights, we created trametiglue, which limits adaptive resistance to MEK inhibition by enhancing interfacial binding. Our results reveal the plasticity of an interface pocket within MEK sub-complexes and have implications for the design of next-generation drugs that target the RAS pathway.
Topics: Amino Acid Sequence; Animals; Binding Sites; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Models, Molecular; Protein Binding; Protein Kinase Inhibitors; Protein Kinases; Pyridones; Pyrimidinones; Substrate Specificity; raf Kinases
PubMed: 32927473
DOI: 10.1038/s41586-020-2760-4 -
International Journal of Molecular... May 2022One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable... (Review)
Review
One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable therapeutics. Conventional therapies in malignant gliomas reconcile surgery and radiotherapy with the use of chemotherapeutic options such as temozolomide, chloroethyl nitrosoureas and the combination therapy of procarbazine, lomustine and vincristine. With the unraveling of deregulated cancer cell signaling pathways, targeted therapies have been developed. The most affected signaling pathways in glioma cells involve tyrosine kinase receptors and their downstream pathways, such as the phosphatidylinositol 3-kinases (PI3K/AKT/mTOR) and mitogen-activated protein kinase pathways (MAPK). MAPK pathway inhibitors include farnesyl transferase inhibitors, Ras kinase inhibitors and mitogen-activated protein extracellular regulated kinase (MEK) inhibitors, while PI3K/AKT/mTOR pathway inhibitors are divided into pan-inhibitors, PI3K/mTOR dual inhibitors and AKT inhibitors. The relevance of the immune system in carcinogenesis has led to the development of immunotherapy, through vaccination, blocking of immune checkpoints, oncolytic viruses, and adoptive immunotherapy using chimeric antigen receptor T cells. In this article we provide a comprehensive review of the signaling pathways underlying malignant transformation, the therapies currently used in the treatment of malignant gliomas and further explore therapies under development, including several ongoing clinical trials.
Topics: Glioma; Humans; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases
PubMed: 35628161
DOI: 10.3390/ijms23105351 -
International Journal of Molecular... Mar 2022Cancer is a leading cause of death worldwide. In many cases, the treatment of the disease is limited due to the metastasis of cells to distant locations of the body... (Review)
Review
Cancer is a leading cause of death worldwide. In many cases, the treatment of the disease is limited due to the metastasis of cells to distant locations of the body through the blood and lymphatic drainage. Most of the anticancer therapeutic options focus mainly on the inhibition of tumor cell growth or the induction of cell death, and do not consider the molecular basis of metastasis. The aim of this work is to provide a comprehensive review focusing on cancer metastasis and the mitogen-activated protein kinase (MAPK) pathway (ERK/JNK/P38 signaling) as a crucial modulator of this process.
Topics: Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Neoplasms; Phosphorylation; p38 Mitogen-Activated Protein Kinases
PubMed: 35409206
DOI: 10.3390/ijms23073847 -
Trends in Parasitology Nov 2022Trypanosomatid parasitic protozoa are divergent from opisthokont models and have evolved unique mechanisms to regulate their complex life cycles and to adapt to a range... (Review)
Review
Trypanosomatid parasitic protozoa are divergent from opisthokont models and have evolved unique mechanisms to regulate their complex life cycles and to adapt to a range of hosts. Understanding how these organisms respond, adapt, and persist in their different hosts could reveal optimal drug-control strategies. Protein kinases are fundamental to many biological processes such as cell cycle control, adaptation to stress, and cellular differentiation. Therefore, we have focused this review on the features and functions of protein kinases that distinguish trypanosomatid kinomes from other eukaryotes. We describe the latest research, highlighting similarities and differences between two groups of trypanosomatid parasites, Leishmania and African trypanosomes.
Topics: Animals; Leishmania; Life Cycle Stages; Protein Kinases; Trypanosoma
PubMed: 36075845
DOI: 10.1016/j.pt.2022.08.009 -
ELife Aug 2019Predicting ancestral sequences of protein kinases reveals the molecular details that underlie different modes of activation.
Predicting ancestral sequences of protein kinases reveals the molecular details that underlie different modes of activation.
Topics: Protein Kinases
PubMed: 31407665
DOI: 10.7554/eLife.49976 -
Molecular Pharmacology Apr 2022Protein kinase A (PKA) is a holoenzyme consisting of a regulatory (R)-subunit dimer and two catalytic (C)-subunits. There are two major families of C-subunits, C and C,... (Review)
Review
Protein kinase A (PKA) is a holoenzyme consisting of a regulatory (R)-subunit dimer and two catalytic (C)-subunits. There are two major families of C-subunits, C and C, and four functionally nonredundant R-subunits (RI, RI, RII, RII). In addition to binding to and being regulated by the R-subunits, the C-subunits are regulated by two tail regions that each wrap around the N- and C-lobes of the kinase core. Although the C-terminal (Ct-) tail is classified as an intrinsically disordered region (IDR), the N-terminal (Nt-) tail is dominated by a strong helix that is flanked by short IDRs. In contrast to the Ct-tail, which is a conserved and highly regulated feature of all PKA, PKG, and protein kinase C protein kinase group (AGC) kinases, the Nt-tail has evolved more recently and is highly variable in vertebrates. Surprisingly and in contrast to the kinase core and the Ct-tail, the entire Nt-tail is not conserved in nonmammalian PKAs. In particular, in humans, C actually represents a large family of C-subunits that are highly variable in their Nt-tail and also expressed in a highly tissue-specific manner. Although we know so much about the C1-subunit, we know almost nothing about these C isoforms wherein C2 is highly expressed in lymphocytes, and C3 and C4 isoforms account for ∼50% of PKA signaling in brain. Based on recent disease mutations, the C proteins appear to be functionally important and nonredundant with the C isoforms. Imaging in retina also supports nonredundant roles for C as well as isoform-specific localization to mitochondria. This represents a new frontier in PKA signaling. SIGNIFICANCE STATEMENT: How tails and adjacent domains regulate each protein kinase is a fundamental challenge for the biological community. Here we highlight how the N- and C-terminal tails of PKA (Nt-tails/Ct-tails) affect the structure and regulate the function of the kinase core and show the combinatorial variations that are introduced into the Nt-tail of the C- and C-subunits in contrast to the Ct-tail, which is conserved across the entire AGC subfamily of protein kinases.
Topics: Animals; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; Cyclic AMP-Dependent Protein Kinases; Humans; Protein Isoforms; Protein Kinases; Signal Transduction
PubMed: 34330820
DOI: 10.1124/molpharm.121.000315 -
International Journal of Molecular... Apr 2023MKK4 (mitogen-activated protein kinase kinase 4; also referred to as MEK4) is a dual-specificity protein kinase that phosphorylates and regulates both JNK (c-Jun... (Review)
Review
MKK4 (mitogen-activated protein kinase kinase 4; also referred to as MEK4) is a dual-specificity protein kinase that phosphorylates and regulates both JNK (c-Jun N-terminal kinase) and p38 MAPK (p38 mitogen-activated protein kinase) signaling pathways and therefore has a great impact on cell proliferation, differentiation and apoptosis. Overexpression of MKK4 has been associated with aggressive cancer types, including metastatic prostate and ovarian cancer and triple-negative breast cancer. In addition, MKK4 has been identified as a key regulator in liver regeneration. Therefore, MKK4 is a promising target both for cancer therapeutics and for the treatment of liver-associated diseases, offering an alternative to liver transplantation. The recent reports on new inhibitors, as well as the formation of a startup company investigating an inhibitor in clinical trials, show the importance and interest of MKK4 in drug discovery. In this review, we highlight the significance of MKK4 in cancer development and other diseases, as well as its unique role in liver regeneration. Furthermore, we present the most recent progress in MKK4 drug discovery and future challenges in the development of MKK4-targeting drugs.
Topics: Female; Humans; Male; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Ovarian Neoplasms; p38 Mitogen-Activated Protein Kinases; Phosphorylation
PubMed: 37108658
DOI: 10.3390/ijms24087495 -
BMC Research Notes Feb 2024The superfamily of protein kinases features a common Protein Kinase-like (PKL) three-dimensional fold. Proteins with PKL structure can also possess enzymatic activities...
OBJECTIVE
The superfamily of protein kinases features a common Protein Kinase-like (PKL) three-dimensional fold. Proteins with PKL structure can also possess enzymatic activities other than protein phosphorylation, such as AMPylation or glutamylation. PKL proteins play a vital role in the world of living organisms, contributing to the survival of pathogenic bacteria inside host cells, as well as being involved in carcinogenesis and neurological diseases in humans. The superfamily of PKL proteins is constantly growing. Therefore, it is crucial to gather new information about PKL families.
RESULTS
To this end, the KINtaro database ( http://bioinfo.sggw.edu.pl/kintaro/ ) has been created as a resource for collecting and sharing such information. KINtaro combines protein sequence information and additional annotations for more than 70 PKL families, including 32 families not associated with PKL superfamily in established protein domain databases. KINtaro is searchable by keywords and by protein sequence and provides family descriptions, sequences, sequence alignments, HMM models, 3D structure models, experimental structures with PKL domain annotations and sequence logos with catalytic residue annotations.
Topics: Humans; Protein Kinases; Proteins; Phosphorylation; Amino Acid Sequence; Sequence Alignment; Databases, Protein
PubMed: 38365785
DOI: 10.1186/s13104-024-06713-y