There's more to death than life: Noncatalytic functions in kinase and pseudokinase signaling.
TL;DR: A review of the non-catalytic functions of protein kinases can be found in this paper, where the authors consider pseudokinases, proteins that are devoid of enzymatic activity altogether and demonstrate that, beyond conventional notions of kinase function, catalytic activity can be dispensable for biological function.
About: This article is published in Journal of Biological Chemistry.The article was published on 2021-01-01 and is currently open access. It has received 40 citations till now. The article focuses on the topics: Kinase activity & Protein kinase A.
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TL;DR: The characterized noncatalytic functions of kinases are summarized, and the recent progress on developing small-molecule modulators of the noncatalyst functions of Kinase catalytic functions are highlighted.
Abstract: Protein kinases have been highly fruitful targets for cancer drug discovery in the past two decades, while most of these drugs bind to the "adenosine triphosphate (ATP)-site" and inhibit kinase catalytic activity. Recently, accumulated evidence suggests that kinases possess functions beyond catalysis through their scaffolds, and the scaffolding functions could play critical roles in multiple cellular signaling and cell fate controls. Small molecules modulating the noncatalytic functions of kinases are rarely reported but emerge as new promising therapeutic strategies for various diseases. Herein, we summarize the characterized noncatalytic functions of kinases, and highlight the recent progress on developing small-molecule modulators of the noncatalytic functions of kinases. Mechanisms and characteristics of different kinds of modulators are also discussed. It is also speculated that targeting the noncatalytic functions would represent a new direction for kinase-based drug discovery.
11 citations
TL;DR: In this paper , the authors summarize and analyze recent progress in blocking non-enzymatic functions of target proteins by PROTAC-mediated degradation, highlighting representative case studies and discussing the pharmacological features originating from inhibition of the non enzymatic function.
Abstract: The non-enzymatic functions of target proteins play key roles in the regulation of various cell signaling pathways and are closely related to numerous human diseases. However, traditional small-molecule inhibitors generally target the catalytic functional domain directly and work by inhibiting the enzymatic function of the target proteins without affecting the non-enzymatic function. The recently emerging proteolysis targeting chimera (PROTAC) technology has the advantage of simultaneously regulating the enzymatic and non-enzymatic functions of target proteins, thus providing a potential strategy to make up for the deficiency of inhibitors and explore the new therapeutic profile by the target degradation. This perspective aims to specifically summarize and analyze recent progress in blocking non-enzymatic functions of target proteins by PROTAC-mediated degradation, highlighting representative case studies and discussing the pharmacological features originating from inhibition of the non-enzymatic functions.
11 citations
TL;DR: In this paper, the authors highlight recent case studies illustrating the development of high-quality chemical probes for less-studied kinases and their application in target validation and discuss the associated challenges and opportunities.
Abstract: Over 20 years after the approval of the first-in-class protein kinase inhibitor imatinib, the biological function of a significant fraction of the human kinome remains poorly understood while most research continues to be focused on few well-validated targets. Given the strong genetic evidence for involvement of many kinases in health and disease, the understudied fraction of the kinome holds a large and unexplored potential for future therapies. Specific chemical probes are indispensable tools to interrogate biology enabling proper preclinical validation of novel kinase targets. In this Perspective, we highlight recent case studies illustrating the development of high-quality chemical probes for less-studied kinases and their application in target validation. We spotlight emerging techniques and approaches employed in the generation of chemical probes for protein kinases and beyond and discuss the associated challenges and opportunities.
10 citations
TL;DR: In this paper , the authors discuss recent structural data on conformational transitions and nucleotide binding by pseudokinases and discuss how biasing this conformational toggle may provide opportunities to target pseudokinase pharmacologically in disease.
6 citations
TL;DR: The TRIB1 family of proteins as discussed by the authors plays important roles in differentiation, development, and oncogenesis, and is known to be accessible to small-molecule inhibitors in spite of its inability to bind ATP.
Abstract: The Tribbles family of proteins-comprising TRIB1, TRIB2, TRIB3 and more distantly related STK40-play important, but distinct, roles in differentiation, development and oncogenesis. Of the four Tribbles proteins, TRIB1 has been most well characterised structurally and plays roles in diverse cancer types. The most well-understood role of TRIB1 is in acute myeloid leukaemia, where it can regulate C/EBP transcription factors and kinase pathways. Structure-function studies have uncovered conformational switching of TRIB1 from an inactive to an active state when it binds to C/EBPα. This conformational switching is centred on the active site of TRIB1, which appears to be accessible to small-molecule inhibitors in spite of its inability to bind ATP. Beyond myeloid neoplasms, TRIB1 plays diverse roles in signalling pathways with well-established roles in tumour progression. Thus, TRIB1 can affect both development and chemoresistance in leukaemia; glioma; and breast, lung and prostate cancers. The pervasive roles of TRIB1 and other Tribbles proteins across breast, prostate, lung and other cancer types, combined with small-molecule susceptibility shown by mechanistic studies, suggests an exciting potential for Tribbles as direct targets of small molecules or biomarkers to predict treatment response.
4 citations
References
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TL;DR: The protein kinase complement of the human genome is catalogued using public and proprietary genomic, complementary DNA, and expressed sequence tag sequences to provide a starting point for comprehensive analysis of protein phosphorylation in normal and disease states and a detailed view of the current state of human genome analysis through a focus on one large gene family.
Abstract: We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.
7,486 citations
TL;DR: Phylogenetic mapping of the conserved protein kinase catalytic domains can serve as a useful first step in the functional characterization of these newly identified family members.
Abstract: In recent years, members of the protein kinase family have been discovered at an accelerated pace. Most were first described, not through the traditional biochemical approach of protein purification and enzyme assay, but as putative protein kinase amino acid sequences deduced from the nucleotide sequences of molecularly cloned genes or complementary DNAs. Phylogenetic mapping of the conserved protein kinase catalytic domains can serve as a useful first step in the functional characterization of these newly identified family members.
4,838 citations
TL;DR: A clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model.
Abstract: Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines(1,2). The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly(3). Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines(4,5). Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (>80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.
3,326 citations
TL;DR: It is demonstrated that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context, which provides new insights into the therapeutic use of ATP- competitive RAF inhibitors.
Abstract: Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects. Small molecule ATP-competitive RAF kinase inhibitors have potent antitumour effects on mutant BRAF(V600E) tumours but, in contrast to mitogen-activated protein kinase kinase (MEK) inhibitors, are not potent against RAS mutant tumour models, despite RAF functioning as a key effector downstream of RAS and upstream of MEK. Here we show that ATP-competitive RAF inhibitors have two opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. Inhibitor binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors.
1,491 citations
TL;DR: Structural-guided mutation of the MLKL pseudoactive site resulted in constitutive, RIPK3-independent necroptosis, demonstrating that modification ofMLKL is essential for propagation of the ne croptosis pathway downstream of RIPK 3.
934 citations