Trends in Cell Biology
Feature ReviewDay of the dead: pseudokinases and pseudophosphatases in physiology and disease
Section snippets
Kinases, phosphatases, and their pseudoenzymatic counterparts
Protein phosphorylation is one of the most abundant post-translational modifications [1], enabling kinase and phosphatase signaling networks to orchestrate a wide range of cellular processes including transcription, metabolism, trafficking, and cytoskeletal dynamics. Consequently, it is not surprising that deregulation of the kinases and phosphatases that regulate these signaling pathways underlies many human diseases. The annotation of the human kinome was a unifying event in the signaling
What are pseudoenzymes, how did they originate, and what are their cellular roles?
Sensu stricto, a pseudoenzyme is a protein that can be classified (usually based on sequence homology) within a mechanistically validated group of enzymes but is totally devoid of catalytic activity. Although this is a straightforward theoretical definition, experimental interpretation of physiological catalysis is rather more complex and could easily apply to unstudied (as opposed to inactive) proteins from any enzyme family. This is especially true for pseudokinases and pseudophosphatases,
The human pseudophosphatome and pseudokinome
The human phosphatome comprises about 215 members which dephosphorylate a huge range of substrates including phosphoproteins, phosphoglycans, and phospholipids [(see the Human Phosphatase Portal (HuPho) database for a complete list (http://hupho.uniroma2.it/)]. In addition, a plethora of regulatory subunits target and regulate each catalytic subunit, vastly increasing their cellular signaling repertoire. Some 17 human phosphatome members (~8% of total) are defined as pseudophosphatases based on
Pseudokinases and pseudophosphatases in human disease
As illustrated above, mechanistic details of the modes of action of various pseudokinases and pseudophosphatases have only recently been revealed, and the majority of these pseudoenzymes remain poorly characterized. In this section we review some evidence for the involvement of pseudokinases and pseudophosphatases in human pathologies, which helps foster the notion that these classes of proteins are promising novel drug targets.
Table 1, Table 2 summarize the localization, disease relevance, and
Concluding remarks
It is becoming clear that pseudokinases and pseudophosphatases are important components of multiple different signal transduction pathways and that they utilize a wide range of mechanisms to regulate cellular homeostasis. In addition, there are numerous reports demonstrating that they represent attractive therapeutic targets. However, there are several hurdles that must be cleared before we can successfully target these proteins pharmacologically. On one hand, our knowledge of the molecular
Acknowledgments
This work was supported by the Swiss National Science Foundation, the German Science Foundation, the Canton of Thurgau, the Royal Society of London, and the University of Konstanz. P.A.E. acknowledges Fiona Bailey and George A. Romero for useful discussions.
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The DUSP domain of pseudophosphatase MK-STYX interacts with G3BP1 to decrease stress granules
2023, Archives of Biochemistry and BiophysicsLooking lively: emerging principles of pseudokinase signaling
2022, Trends in Biochemical SciencesCitation Excerpt :This observation suggested the existence of a class of pseudokinases that are incapable of catalyzing phosphotransfer. The fact that these pseudokinases are conserved across species [5] also argues that they may have evolved new non-catalytic functions [6,7]. The past two decades have seen significant progress both in understanding pseudokinases themselves [8] and in appreciating the non-catalytic functions of their bona fide kinase relatives [9].
CRISPR deletions in cell lines for reconstitution studies of pseudokinase function
2022, Methods in EnzymologyA suite of in vitro and in vivo assays for monitoring the activity of the pseudokinase Bud32
2022, Methods in EnzymologyCitation Excerpt :This transfer event is facilitated by a catalytic Asp residue within a canonical His-Arg-Asp (HRD) motif in a region termed the catalytic loop. Somewhat surprisingly, a considerable portion of the protein kinase family are classified as pseudokinases and function by other non-conventional mechanisms (Boudeau, Miranda-Saavedra, Barton, & Alessi, 2006; Jacobsen & Murphy, 2017; Kung & Jura, 2016; Reiterer et al., 2014). In humans for example, ~ 10% of all protein kinases are considered to be pseudokinases (Kung & Jura, 2016).
Computational tools and resources for pseudokinase research
2022, Methods in EnzymologyModulating undruggable targets to overcome cancer therapy resistance
2022, Drug Resistance Updates