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

•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.