-
Chemical Society Reviews Apr 2018Protein kinases are involved in the regulation of many cellular processes including cell differentiation, survival, migration, axon guidance and neuronal plasticity. A... (Review)
Review
Protein kinases are involved in the regulation of many cellular processes including cell differentiation, survival, migration, axon guidance and neuronal plasticity. A growing set of optogenetic tools, termed opto-kinases, allows activation and inhibition of different protein kinases with light. The optogenetic regulation enables fast, reversible and non-invasive manipulation of protein kinase activities, complementing traditional methods, such as treatment with growth factors, protein kinase inhibitors or chemical dimerizers. In this review, we summarize the properties of the existing optogenetic tools for controlling tyrosine kinases and serine-threonine kinases. We discuss how the opto-kinases can be applied for studies of spatial and temporal aspects of protein kinase signaling in cells and organisms. We compare approaches for chemical and optogenetic regulation of protein kinase activity and present guidelines for selection of opto-kinases and equipment to control them with light. We also describe strategies to engineer novel opto-kinases on the basis of various photoreceptors.
Topics: Animals; Humans; Optogenetics; Protein Kinases; Signal Transduction
PubMed: 29498733
DOI: 10.1039/c7cs00404d -
Expert Review of Anticancer Therapy Dec 2018Protein kinases are involved in various cellular functions. About 2% of the human genome encodes for protein kinases. Dysregulation of protein kinases is implicated in... (Review)
Review
Protein kinases are involved in various cellular functions. About 2% of the human genome encodes for protein kinases. Dysregulation of protein kinases is implicated in various processes of carcinogenesis. The advent of protein kinase inhibitors in cancer therapy has led to a paradigm shift in cancer therapy. Several protein kinase inhibitors have been approved by FDA in the last few decades. Areas covered: This article provides a review of the FDA approved protein kinase inhibitors as of December 2017 for the well-known oncogenic protein kinases. A list of FDA approved protein kinase inhibitors and their FDA approved clinical indications were cataloged. The role of the respective oncogenic protein kinases in carcinogenesis and cancer progression and the relevant landmark clinical trials of respective protein kinase inhibitors leading up to the FDA approval were PubMed searched and discussed. Expert commentary: Further understanding of the molecular origin of various cancers would help identify new targets. Use of biomarker profiling might select the patient population that would benefit better from kinase inhibitors. Clinical trials should be designed to identify the appropriate sequence of the available kinase inhibitors. It would prove to be useful to test these drugs in the adjuvant setting.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Disease Progression; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Kinases
PubMed: 30259761
DOI: 10.1080/14737140.2018.1527688 -
Genes Jun 2023Tremendous amount of financial resources and manpower have been invested to understand the function of numerous genes that are deregulated during the carcinogenesis... (Review)
Review
Tremendous amount of financial resources and manpower have been invested to understand the function of numerous genes that are deregulated during the carcinogenesis process, which can be targeted for anticancer therapeutic interventions. () is one of the genes that have shown potential as biomarkers for cancer treatment. It is a member of the kinase family, which also includes Death-associated protein kinase 2 (DAPK-2), Death-associated protein kinase 3 (DAPK-3), Death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK-1) and Death-associated protein kinase-related apoptosis-inducing kinase 2 (DRAK-2). is a tumour-suppressor gene that is hypermethylated in most human cancers. Additionally, DAPK-1 regulates a number of cellular processes, including apoptosis, autophagy and the cell cycle. The molecular basis by which DAPK-1 induces these cell homeostasis-related processes for cancer prevention is less understood; hence, they need to be investigated. The purpose of this review is to discuss the current understanding of the mechanisms of DAPK-1 in cell homeostasis-related processes, especially apoptosis, autophagy and the cell cycle. It also explores how the expression of DAPK-1 affects carcinogenesis. Since deregulation of DAPK-1 is implicated in the pathogenesis of cancer, altering DAPK-1 expression or activity may be a promising therapeutic strategy against cancer.
Topics: Humans; Death-Associated Protein Kinases; Calcium-Calmodulin-Dependent Protein Kinases; Apoptosis Regulatory Proteins; Apoptosis; Neoplasms; Carcinogenesis
PubMed: 37372454
DOI: 10.3390/genes14061274 -
Experimental & Molecular Medicine Jun 2021Necroptosis is a form of programmed necrosis that is mediated by various cytokines and pattern recognition receptors (PRRs). Cells dying by necroptosis show necrotic... (Review)
Review
Necroptosis is a form of programmed necrosis that is mediated by various cytokines and pattern recognition receptors (PRRs). Cells dying by necroptosis show necrotic phenotypes, including swelling and membrane rupture, and release damage-associated molecular patterns (DAMPs), inflammatory cytokines, and chemokines, thereby mediating extreme inflammatory responses. Studies on gene knockout or necroptosis-specific inhibitor treatment in animal models have provided extensive evidence regarding the important roles of necroptosis in inflammatory diseases. The necroptosis signaling pathway is primarily modulated by activation of receptor-interacting protein kinase 3 (RIPK3), which phosphorylates mixed-lineage kinase domain-like protein (MLKL), mediating MLKL oligomerization. In the necroptosis process, these proteins are fine-tuned by posttranslational regulation via phosphorylation, ubiquitination, glycosylation, and protein-protein interactions. Herein, we review recent findings on the molecular regulatory mechanisms of necroptosis.
Topics: Animals; Apoptosis; Necroptosis; Necrosis; Phosphorylation; Protein Kinases
PubMed: 34075202
DOI: 10.1038/s12276-021-00634-7 -
Biochemistry Oct 2016The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the... (Review)
Review
The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the Saccharomyces cerevisiae protein kinase Ste20, their most characteristic feature is the presence near the carboxy terminus of a unique helical structure called a SARAH domain; this segment allows MST1/MST2 to homodimerize and to heterodimerize with the other polypeptides that contain SARAH domains, the noncatalytic polypeptides RASSF1-6 and Sav1/WW45. Early studies emphasized the potent ability of MST1/MST2 to induce apoptosis upon being overexpressed, as well as the conversion of the endogenous MST1/MST2 polypeptides to constitutively active, caspase-cleaved catalytic fragments during apoptosis initiated by any stimulus. Later, the cleaved, constitutively active form of MST1 was identified in nonapoptotic, quiescent adult hepatocytes as well as in cells undergoing terminal differentiation, where its presence is necessary to maintain those cellular states. The physiologic regulation of full length MST1/MST2 is controlled by the availability of its noncatalytic SARAH domain partners. Interaction with Sav1/WW45 recruits MST1/MST2 into a tumor suppressor pathway, wherein it phosphorylates and activates the Sav1-bound protein kinases Lats1/Lats2, potent inhibitors of the Yap1 and TAZ oncogenic transcriptional regulators. A constitutive interaction with the Rap1-GTP binding protein RASSF5B (Nore1B/RAPL) in T cells recruits MST1 (especially) and MST2 as an effector of Rap1's control of T cell adhesion and migration, a program crucial to immune surveillance and response; loss of function mutation in human MST1 results in profound immunodeficiency. MST1 and MST2 are also regulated by other protein kinases, positively by TAO1 and negatively by Par1, SIK2/3, Akt, and cRaf1. The growing list of candidate MST1/MST2 substrates suggests that the full range of MST1/MST2's physiologic programs and contributions to pathophysiology remains to be elucidated.
Topics: Animals; Apoptosis; Catalysis; Enzyme Activation; Humans; Liver; Mitosis; Phosphorylation; Protein Conformation; Protein Kinases; Reactive Oxygen Species; Substrate Specificity; Tyrosine
PubMed: 27618557
DOI: 10.1021/acs.biochem.6b00763 -
World Journal of Gastroenterology Aug 2021Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new... (Review)
Review
Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.
Topics: Apoptosis; Humans; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; p38 Mitogen-Activated Protein Kinases
PubMed: 34497429
DOI: 10.3748/wjg.v27.i30.4963 -
Molecular Biology and Evolution Jan 2015Heat-shock protein 90 (Hsp90) promotes the maturation and stability of its client proteins, including many kinases. In doing so, Hsp90 may allow its clients to...
Heat-shock protein 90 (Hsp90) promotes the maturation and stability of its client proteins, including many kinases. In doing so, Hsp90 may allow its clients to accumulate mutations as previously proposed by the capacitor hypothesis. If true, Hsp90 clients should show increased evolutionary rate compared with nonclients; however, other factors, such as gene expression and protein connectivity, may confound or obscure the chaperone's putative contribution. Here, we compared the evolutionary rates of many Hsp90 clients and nonclients in the human protein kinase superfamily. We show that Hsp90 client status promotes evolutionary rate independently of, but in a small magnitude similar to that of gene expression and protein connectivity. Hsp90's effect on kinase evolutionary rate was detected across mammals, specifically relaxing purifying selection. Hsp90 clients also showed increased nucleotide diversity and harbored more damaging variation than nonclient kinases across humans. These results are consistent with the central argument of the capacitor hypothesis that interaction with the chaperone allows its clients to harbor genetic variation. Hsp90 client status is thought to be highly dynamic with as few as one amino acid change rendering a protein dependent on the chaperone. Contrary to this expectation, we found that across protein kinase phylogeny Hsp90 client status tends to be gained, maintained, and shared among closely related kinases. We also infer that the ancestral protein kinase was not an Hsp90 client. Taken together, our results suggest that Hsp90 played an important role in shaping the kinase superfamily.
Topics: Animals; Evolution, Molecular; HSP90 Heat-Shock Proteins; Humans; Mammals; Molecular Chaperones; Mutation Rate; Phylogeny; Protein Kinases; Selection, Genetic
PubMed: 25246701
DOI: 10.1093/molbev/msu270 -
Autophagy Feb 2022The removal of mitochondria in a programmed or stress-induced manner is essential for maintaining cellular homeostasis. To date, much research has focused upon...
The removal of mitochondria in a programmed or stress-induced manner is essential for maintaining cellular homeostasis. To date, much research has focused upon stress-induced mitophagy that is largely regulated by the E3 ligase PRKN, with limited insight into the mechanisms regulating basal "housekeeping" mitophagy levels in different model organisms. Using iron chelation as an inducer of PRKN-independent mitophagy, we recently screened an siRNA library of lipid-binding proteins and determined that two kinases, GAK and PRKCD, act as positive regulators of PRKN-independent mitophagy. We demonstrate that PRKCD is localized to mitochondria and regulates recruitment of ULK1-ATG13 upon induction of mitophagy. GAK activity, by contrast, modifies the mitochondrial network and lysosomal morphology that compromise efficient transport of mitochondria for degradation. Impairment of either kinase blocks basal mitophagy, demonstrating the biological relevance of our findings. CCCP: carbonyl cyanide-m-chlorophenyl hydrazone; DFP: deferiprone; GAK: cyclin G associated kinase; HIF1A: hypoxia inducible factor 1 subunit alpha; PRKC/PKC: protein kinase C; PRKCD: protein kinase C delta; PRKN: parkin RBR E3 ubiquitin protein ligase.
Topics: Autophagy; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Mitophagy; Protein Kinase C-delta; Protein Kinases; Ubiquitin-Protein Ligases
PubMed: 35001811
DOI: 10.1080/15548627.2021.2015154 -
Drug Research Apr 2023Protein kinases belong to the phosphor-transferases superfamily of enzymes, which "activate" enzymes via phosphorylation. The kinome of an organism is the total set of... (Review)
Review
Protein kinases belong to the phosphor-transferases superfamily of enzymes, which "activate" enzymes via phosphorylation. The kinome of an organism is the total set of genes in the genome, which encode for all the protein kinases. Certain mutations in the kinome have been linked to dysregulation of protein kinases, which in turn can lead to several diseases and disorders including cancer. In this review, we have briefly discussed the role of protein kinases in various biochemical processes by categorizing cancer associated phenotypes and giving their protein kinase examples. Various techniques have also been discussed, which are being used to analyze the structure of protein kinases, and associate their roles in the oncogenesis. We have also discussed protein kinase inhibitors and United States Federal Drug Administration (USFDA) approved drugs, which target protein kinases and can serve as a counter to protein kinase dysregulation and mitigate the effects of oncogenesis. Overall, this review briefs about the importance of protein kinases, their roles in oncogenesis on dysregulation and how their inhibition via various drugs can be used to mitigate their effects.
Topics: Humans; Protein Kinases; Protein Kinase Inhibitors; Neoplasms; Carcinogenesis
PubMed: 36822216
DOI: 10.1055/a-1989-1856 -
Autophagy Jun 2021Macroautophagy/autophagy is the cellular process responsible for the elimination and recycling of aggregated proteins and damaged organelles. Whereas autophagy is...
Macroautophagy/autophagy is the cellular process responsible for the elimination and recycling of aggregated proteins and damaged organelles. Whereas autophagy is strictly regulated by several signaling cascades, the link between this process and the subcellular distribution of its regulatory pathways remains to be established. Our recent work suggests that the compartmentalization of PRKA/PKA (protein kinase cAMP-activated) determines its effects on autophagy. We found that increased cAMP levels generate dramatically different PRKA activity "signatures" mainly dependent on the actions of phosphatases and the distribution of the PRKA holoenzymes containing type II regulatory subunits (PRKAR2A and PRKAR2B; RII). In this punctum we discuss how compartmentalized PRKA signaling events are generated and affect the autophagic flux in specific cell types.
Topics: Autophagy; Phosphoric Monoester Hydrolases; Protein Kinases; Proteins; Signal Transduction
PubMed: 33971785
DOI: 10.1080/15548627.2021.1924501