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Tribbles Pseudokinases in Colorectal Cancer.

ABSTRACT: The Tribbles family of pseudokinases controls a wide number of processes during cancer on-set and progression. However, the exact contribution of each of the three family members is still to be defined. Their function appears to be context-dependent as they can act as oncogenes or tumor suppressor genes. They act as scaffolds modulating the activity of several signaling pathways involved in different cellular processes. In this review, we discuss the state-of-knowledge for TRIB1, TRIB2 and TRIB3 in the development and progression of colorectal cancer. We take a perspective look at the role of Tribbles proteins as potential biomarkers and therapeutic targets. Specifically, we chronologically systematized all available articles since 2003 until 2020, for which Tribbles were associated with colorectal cancer human samples or cell lines. Herein, we discuss: (1) Tribbles amplification and overexpression; (2) the clinical significance of Tribbles overexpression; (3) upstream Tribbles gene and protein expression regulation; (4) Tribbles pharmacological modulation; (5) genetic modulation of Tribbles; and (6) downstream mechanisms regulated by Tribbles; establishing a comprehensive timeline, essential to better consolidate the current knowledge of Tribbles' role in colorectal cancer.

SUBMITTER: Ferreira BI

PROVIDER: S-EPMC8201230 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease.

Project description:The Tribbles (TRIB) pseudokinases control multiple aspects of eukaryotic cell biology and evolved unique features distinguishing them from all other protein kinases. The atypical pseudokinase domain retains a regulated binding platform for substrates, which are ubiquitinated by context-specific E3 ligases. This plastic configuration has also been exploited as a scaffold to support the modulation of canonical MAPK and AKT modules. In this review, we discuss the evolution of TRIBs and their roles in vertebrate cell biology. TRIB2 is the most ancestral member of the family, whereas the emergence of TRIB3 homologs in mammals supports additional biological roles, many of which are currently being dissected. Given their pleiotropic role in diseases, the unusual TRIB pseudokinase conformation provides a highly attractive opportunity for drug design.

| S-EPMC5382568 | biostudies-literature

Tribbles Pseudokinase 3 Regulation and Contribution to Cancer.

Project description:The first Tribbles protein was identified as critical for the coordination of morphogenesis in Drosophila melanogaster. Three mammalian homologs were subsequently identified, with a structure similar to classic serine/threonine kinases, but lacking crucial amino acids for the catalytic activity. Thereby, the very weak ATP affinity classifies TRIB proteins as pseudokinases. In this review, we provide an overview of the regulation of TRIB3 gene expression at both transcriptional and post-translational levels. Despite the absence of kinase activity, TRIB3 interferes with a broad range of cellular processes through protein-protein interactions. In fact, TRIB3 acts as an adaptor/scaffold protein for many other proteins such as kinase-dependent proteins, transcription factors, ubiquitin ligases, or even components of the spliceosome machinery. We then state the contribution of TRIB3 to cancer development, progression, and metastasis. TRIB3 dysregulation can be associated with good or bad prognosis. Indeed, as TRIB3 interacts with and regulates the activity of many key signaling components, it can act as a tumor-suppressor or oncogene in a context-dependent manner.

| S-EPMC8070086 | biostudies-literature

Recent advances in targeting protein kinases and pseudokinases in cancer biology.

Project description:Kinases still remain the most favorable members of the druggable genome, and there are an increasing number of kinase inhibitors approved by the FDA to treat a variety of cancers. Here, we summarize recent developments in targeting kinases and pseudokinases with some examples. Targeting the cell cycle machinery garnered significant clinical success, however, a large section of the kinome remains understudied. We also review recent developments in the understanding of pseudokinases and discuss approaches on how to effectively target in cancer.

| S-EPMC9354965 | biostudies-literature

Nucleotide-binding mechanisms in pseudokinases.

Project description:Pseudokinases are classified by the lack of one or several of the highly conserved motifs involved in nucleotide (nt) binding or catalytic activity of protein kinases (PKs). Pseudokinases represent ∼10% of the human kinome and they are found in all evolutionary classes of kinases. It has become evident that pseudokinases, which were initially considered somewhat peculiar dead kinases, are important components in several signalling cascades. Furthermore, several pseudokinases have been linked to human diseases, particularly cancer, which is raising interest for therapeutic approaches towards these proteins. The ATP-binding pocket is a well-established drug target and elucidation of the mechanism and properties of nt binding in pseudokinases is of significant interest and importance. Recent studies have demonstrated that members of the pseudokinase family are very diverse in structure as well as in their ability and mechanism to bind nts or perform phosphoryl transfer reactions. This diversity also precludes prediction of pseudokinase function, or the importance of nt binding for said function, based on primary sequence alone. Currently available data indicate that ∼40% of pseudokinases are able to bind nts, whereas only few are able to catalyse occasional phosphoryl transfer. Pseudokinases employ diverse mechanisms to bind nts, which usually occurs at low, but physiological, affinity. ATP binding serves often a structural role but in most cases the functional roles are not precisely known. In the present review, we discuss the various mechanisms that pseudokinases employ for nt binding and how this often low-affinity binding can be accurately analysed.

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Prospects for pharmacological targeting of pseudokinases.

Project description: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.

| S-EPMC7813639 | biostudies-literature

Trouble With Tribbles-1.

Project description:Genome-wide association studies (GWAS) have identified hundreds of genomic loci in humans that are significantly associated with plasma cholesterol, triglycerides, and coronary artery disease. Although some loci contain genes with known regulatory roles in lipid metabolism and atherosclerosis, the majority were being implicated for the first time. The 8q24 locus, containing the gene TRIB1 ( Tribbles-1), is the only novel GWAS locus that associates with all 4 plasma lipid traits and coronary artery disease, an observation that has spurred immense interest in this locus. Subsequent in vivo loss and gain of function studies confirmed that Trib1 plays a role in hepatic lipid metabolism, validating the initial genetic observation. Yet, many challenges remain in discerning the nature of the association between the TRIB1 locus and cardiometabolic phenotypes. Is TRIB1 the causal gene at the 8q24 locus and what is the functional consequence of the associated noncoding variation? Is the relationship between TRIB1 and the transcription factor C/EBP? (CCAAT/enhancer-binding protein alpha) the primary molecular mechanism governing the genetic association or could it be an as yet unknown function for this interesting pseudokinase? Is hepatic TRIB1 the sole regulator of lipid metabolism or could extrahepatic TRIB1 play a role as well? The following review summarizes key findings related to these questions and highlights both the challenges and excitement in pursuing translational research of a novel gene in the post-GWAS era.

| S-EPMC6761832 | biostudies-literature

STRAD pseudokinases regulate axogenesis and LKB1 stability.

Project description:Neuronal polarization is an essential step of morphogenesis and connectivity in the developing brain. The serine/threonine kinase LKB1 is a key regulator of cell polarity, metabolism, tumorigenesis, and is required for axon formation. It is allosterically regulated by two related and evolutionarily conserved pseudokinases, STe20-Related ADapters (STRADs) ? and ?. The roles of STRAD? and STRAD? in the developing nervous system are not fully defined, nor is it known whether they serve distinct functions.We find that STRAD? is highly spliced and appears to be the primal STRAD paralog. We report that each STRAD is sufficient for axogenesis and promoting cell survival in the developing cortex. We also reveal a reciprocal protein-stabilizing relationship in vivo between LKB1 and STRAD?, whereby STRAD? specifically maintains LKB1 protein levels via cytoplasmic compartmentalization.We demonstrate a novel role for STRAD? in axogenesis and also show for the first time in vivo that STRAD?, but not STRAD?, is responsible for LKB1 protein stability.

| S-EPMC4016016 | biostudies-literature

Methods for discovering catalytic activities for pseudokinases.

Project description:Pseudoenzymes resemble active enzymes, but lack key catalytic residues believed to be required for activity. Many pseudoenzymes appear to be inactive in conventional enzyme assays. However, an alternative explanation for their apparent lack of activity is that pseudoenzymes are being assayed for the wrong reaction. We have discovered several new protein kinase-like families which have revealed how different binding orientations of adenosine triphosphate (ATP) and active site residue migration can generate a novel reaction from a common kinase scaffold. These results have exposed the catalytic versatility of the protein kinase fold and suggest that atypical kinases and pseudokinases should be analyzed for alternative transferase activities. In this chapter, we discuss a general approach for bioinformatically identifying divergent or atypical members of an enzyme superfamily, then present an experimental approach to characterize their catalytic activity.

| S-EPMC9554938 | biostudies-literature

Pseudokinases-remnants of evolution or key allosteric regulators?

Project description:Protein kinases provide a platform for the integration of signal transduction networks. A key feature of transmitting these cellular signals is the ability of protein kinases to activate one another by phosphorylation. A number of kinases are predicted by sequence homology to be incapable of phosphoryl group transfer due to degradation of their catalytic motifs. These are termed pseudokinases and because of the assumed lack of phosphoryltransfer activity their biological role in cellular transduction has been mysterious. Recent structure-function studies have uncovered the molecular determinants for protein kinase inactivity and have shed light to the biological functions and evolution of this enigmatic subset of the human kinome. Pseudokinases act as signal transducers by bringing together components of signalling networks, as well as allosteric activators of active protein kinases.

| S-EPMC3014569 | biostudies-literature

Tribbles Pseudokinase 3 Contributes to Cancer Stemness of Endometrial Cancer Cells by Regulating ?-Catenin Expression.

Project description:Endometrial cancer (EC) is the second most common gynecological malignancy worldwide. Tribbles pseudokinase 3 (TRIB3) is a scaffolding protein that regulates intracellular signal transduction, and its role in tumor development is controversial. Here, we investigated the biological function of TRIB3 in EC. We found that the messenger RNA (mRNA) expression level of TRIB3 was significantly and positively correlated with shorter overall survival of EC patients in The Cancer Genome Atlas database. The protein expression of TRIB3 was found to be significantly increased in EC cancer stem cells (CSCs) enriched by tumorsphere cultivation. Knockdown of TRIB3 in EC cells suppressed tumorsphere formation, the expression of cancer stemness genes, and the in vivo tumorigenesis. The expression of ?-catenin at both the protein and the mRNA levels was downregulated upon TRIB3 silencing. TRIB3 was found to interact with E74 Like ETS transcription factor 4 (ELF4) in the nucleus and bound to ELF4 consensus sites within the catenin beta 1 (CTNNB1) promoter in EC cell lines. These data indicated that TRIB3 may regulate CTNNB1 transcription by enhancing the recruitment of ELF4 to the CTNNB1 promoter. In conclusion, our results suggest that TRIB3 plays an oncogenic role in EC and positively regulates the self-renewal and tumorigenicity of EC-CSCs. Targeting TRIB3 is considered as a potential therapeutic strategy in future EC therapy.

| S-EPMC7765506 | biostudies-literature

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