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Expert Reviews in Molecular Medicine Jan 2012New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase... (Review)
Review
New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetes mellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesity and diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the exception of metformin, which is considered to function mainly by activating AMPK, no treatment for the metabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapies based on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatment of diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signal transduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, and we also discuss current clinical implications.
Topics: AMP-Activated Protein Kinase Kinases; Animals; Glucose; Homeostasis; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Protein Kinases; Signal Transduction
PubMed: 22233681
DOI: 10.1017/S1462399411002109 -
Nature Reviews. Cancer Aug 2009In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity....
In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity. LKB1 encodes a serine-threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes. The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.
Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Blood Glucose; Disease Models, Animal; Humans; Hypoglycemic Agents; Mice; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 19629071
DOI: 10.1038/nrc2676 -
Biochemical Society Transactions Feb 2021The protein kinase C-related kinase (PRK) family of serine/threonine kinases, PRK1, PRK2 and PRK3, are effectors for the Rho family small G proteins. An array of studies... (Review)
Review
The protein kinase C-related kinase (PRK) family of serine/threonine kinases, PRK1, PRK2 and PRK3, are effectors for the Rho family small G proteins. An array of studies have linked these kinases to multiple signalling pathways and physiological roles, but while PRK1 is relatively well-characterized, the entire PRK family remains understudied. Here, we provide a holistic overview of the structure and function of PRKs and describe the molecular events that govern activation and autoregulation of catalytic activity, including phosphorylation, protein interactions and lipid binding. We begin with a structural description of the regulatory and catalytic domains, which facilitates the understanding of their regulation in molecular detail. We then examine their diverse physiological roles in cytoskeletal reorganization, cell adhesion, chromatin remodelling, androgen receptor signalling, cell cycle regulation, the immune response, glucose metabolism and development, highlighting isoform redundancy but also isoform specificity. Finally, we consider the involvement of PRKs in pathologies, including cancer, heart disease and bacterial infections. The abundance of PRK-driven pathologies suggests that these enzymes will be good therapeutic targets and we briefly report some of the progress to date.
Topics: Animals; Catalysis; Humans; Protein Conformation; Protein Kinase C; Protein Kinases; Signal Transduction; Structure-Activity Relationship
PubMed: 33522581
DOI: 10.1042/BST20200466 -
Trends in Biochemical Sciences Apr 2019Since publication of the crystal structure of protein kinase (PK)A three decades ago, a structural portrait of the conserved kinase core has been drawn. The next... (Review)
Review
Since publication of the crystal structure of protein kinase (PK)A three decades ago, a structural portrait of the conserved kinase core has been drawn. The next challenge is to elucidate structures of full-length kinases and to address the intrinsically disordered regions (IDRs) that typically flank the core as well as the small linear motifs (SLiMs) that are embedded within the IDRs. It is increasingly apparent that unstructured regions integrate the kinase catalytic chassis into multienzyme-based regulatory networks. The extracellular signal-regulated kinase-ribosomal S6 PK-phosphoinositide-dependent kinase (ERK-RSK-PDK) complex is an excellent example to demonstrate how IDRs and SLiMs govern communication between four different kinase catalytic cores to mediate activation and how in molecular terms these promote the formation of kinase heterodimers in a context dependent fashion.
Topics: Humans; Intrinsically Disordered Proteins; Models, Molecular; Protein Domains; Protein Kinases
PubMed: 30611608
DOI: 10.1016/j.tibs.2018.12.002 -
European Journal of Medicinal Chemistry May 2024The continued growth of data from biological screening and medicinal chemistry provides opportunities for data-driven experimental design and decision making in... (Review)
Review
The continued growth of data from biological screening and medicinal chemistry provides opportunities for data-driven experimental design and decision making in early-phase drug discovery. Approaches adopted from data science help to integrate internal and public domain data and extract knowledge from historical in-house data. Protein kinase (PK) drug discovery is an exemplary area where large amounts of data are accumulating, providing a valuable knowledge base for discovery projects. Herein, the evolution of PK drug discovery and development of small molecular PK inhibitors (PKIs) is reviewed, highlighting milestone developments in the field and discussing exemplary studies providing a basis for increasing data orientation of PK discovery efforts.
Topics: Drug Discovery; Protein Kinase Inhibitors; Humans; Protein Kinases; Molecular Structure
PubMed: 38636127
DOI: 10.1016/j.ejmech.2024.116413 -
Nature Reviews. Drug Discovery Jul 2019Pseudokinases are members of the protein kinase superfamily but signal primarily through noncatalytic mechanisms. Many pseudokinases contribute to the pathologies of... (Review)
Review
Pseudokinases are members of the protein kinase superfamily but signal primarily through noncatalytic mechanisms. Many pseudokinases contribute to the pathologies of human diseases, yet they remain largely unexplored as drug targets owing to challenges associated with modulation of their biological functions. Our understanding of the structure and physiological roles of pseudokinases has improved substantially over the past decade, revealing intriguing similarities between pseudokinases and their catalytically active counterparts. Pseudokinases often adopt conformations that are analogous to those seen in catalytically active kinases and, in some cases, can also bind metal cations and/or nucleotides. Several clinically approved kinase inhibitors have been shown to influence the noncatalytic functions of active kinases, providing hope that similar properties in pseudokinases could be pharmacologically regulated. In this Review, we discuss known roles of pseudokinases in disease, their unique structural features and the progress that has been made towards developing pseudokinase-directed therapeutics.
Topics: Animals; Binding Sites; Humans; Molecular Conformation; Molecular Structure; Molecular Targeted Therapy; Protein Binding; Protein Kinase Inhibitors; Protein Kinases; Small Molecule Libraries
PubMed: 30850748
DOI: 10.1038/s41573-019-0018-3 -
Trends in Pharmacological Sciences Nov 2019Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary... (Review)
Review
Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary kinase classes, the eukaryotic protein kinases (ePKs) and the atypical protein kinases (aPKs), and provides a structure-centered comparison of their sequences, structures, hydrophobic spines, mutation and SNP hotspots, and inhibitor interaction patterns. Despite the limited sequence similarity between these two classes, atypical kinases commonly share the archetypical kinase fold but lack conserved eukaryotic kinase motifs and possess altered hydrophobic spines. Furthermore, atypical kinase inhibitors explore only a limited number of binding modes both inside and outside the orthosteric binding site. The distribution of genetic variations in both classes shows multiple ways they can interfere with kinase inhibitor binding. This multilayered review provides a research framework bridging the eukaryotic and atypical kinase classes.
Topics: Amino Acid Sequence; Antineoplastic Agents; Binding Sites; Humans; Models, Molecular; Neoplasms; Polymorphism, Single Nucleotide; Protein Conformation, beta-Strand; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship
PubMed: 31677919
DOI: 10.1016/j.tips.2019.09.002 -
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 -
The Biochemical Journal Aug 2004Intracellular reactive oxygen species are generated as a by-product of normal metabolic processes and can both damage cellular constituents and function as important... (Review)
Review
Intracellular reactive oxygen species are generated as a by-product of normal metabolic processes and can both damage cellular constituents and function as important signalling species. This signalling often involves changes in the thiol redox balance. As an antioxidant, glutathione serves in maintaining the reduced state of cellular protein thiol groups. The paper by Cross and Templeton appearing in this issue of the Biochemical Journal describes a mechanism by which glutathionylation plays a key role in the regulation of the kinase activity of MEKK1 [MAP (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase kinase; MAP3K] in response to oxidative stresses. This type of post-translational-modification glutathionylation may represent a general mechanism by which protein kinase function can be regulated.
Topics: Glutathione; Protein Kinases
PubMed: 15270699
DOI: 10.1042/BJ20040873 -
International Journal of Molecular... Aug 2017Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in... (Review)
Review
Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in almost all physiological and pathological conditions. Mitosis is a key event during the cell cycle, in which the cell divides into two daughter cells. Autophagy is a process in which the cell digests its own cellular contents. Although autophagy regulation has mainly been studied in asynchronous cells, increasing evidence indicates that autophagy is in fact tightly regulated in mitosis. Here in this review, we will discuss kinases that were originally identified to be involved in only one of either mitosis or autophagy, but were later found to participate in both processes, such as CDKs (cyclin-dependent kinases), Aurora kinases, PLK-1 (polo-like kinase 1), BUB1 (budding uninhibited by benzimidazoles 1), MAPKs (mitogen-activated protein kinases), mTORC1 (mechanistic target of rapamycin complex 1), AMPK (AMP-activated protein kinase), PI3K (phosphoinositide-3 kinase) and protein kinase B (AKT). By focusing on kinases involved in both autophagy and mitosis, we will get a more comprehensive understanding about the reciprocal regulation between the two key cellular events, which will also shed light on their related therapeutic investigations.
Topics: Animals; Autophagy; Humans; Mitosis; Protein Kinases
PubMed: 28858266
DOI: 10.3390/ijms18091884