Trends in Cell Biology
Volume 24, Issue 9, September 2014, Pages 489-505
Journal home page for Trends in Cell Biology

Feature Review
Day of the dead: pseudokinases and pseudophosphatases in physiology and disease

https://doi.org/10.1016/j.tcb.2014.03.008Get rights and content

Highlights

  • Pseudokinases and pseudophosphatases are important in health and disease.

  • They regulate the activity of catalytically competent kinases and phosphatases.

  • They may act as spatial anchors.

  • Via modular domain organization, they may act as scaffolds and signal integrators.

Pseudophosphatases and pseudokinases are increasingly viewed as integral elements of signaling pathways, and there is mounting evidence that they have frequently retained the ability to interact with cellular ‘substrates’, and can exert important roles in different diseases. However, these pseudoenzymes have traditionally received scant attention compared to classical kinases and phosphatases. In this review we explore new findings in the emerging pseudokinase and pseudophosphatase fields, and discuss their different modes of action which include exciting new roles as scaffolds, anchors, spatial modulators, traps, and ligand-driven regulators of canonical kinases and phosphatases. Thus, it is now apparent that pseudokinases and pseudophosphatases both support and drive a panoply of signaling networks. Finally, we highlight recent evidence on their involvement in human pathologies, marking them as potential novel drug targets.

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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