There's more to death than life: non-catalytic functions in kinase and pseudokinase signaling.

Protein kinases are present in all domains of life and play diverse roles in cellular signaling. Whereas the impact of substrate phosphorylation by protein kinases has long been appreciated, it is becoming increasingly clear that protein kinases also play other, non-catalytic, functions. Here, we review recent developments in understanding the non-catalytic functions of protein kinases. Many non-catalytic activities are best exemplified by protein kinases that are devoid of enzymatic activity altogether - known as pseudokinases. These dead proteins illustrate that, beyond conventional notions of kinase function, catalytic activity can be dispensable for biological function. Through key examples we illustrate diverse mechanisms of non-catalytic kinase activity: as allosteric modulators; protein-based switches; scaffolds for complex assembly; and as competitive inhibitors in signaling pathways. In common, these non-catalytic mechanisms exploit the nature of the protein kinase fold as a versatile protein-protein interaction module. Many examples are also intrinsically linked to the ability of the protein kinase to switch between multiple states, a function shared with catalytic protein kinases. Finally, we consider the contemporary landscape of small molecules to modulate non-catalytic functions of protein kinases, which, although challenging, has significant potential given the scope of non-catalytic protein kinase function in health and disease.