There's more to death than life: Noncatalytic 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, noncatalytic, functions. Here, we review recent developments in understanding the noncatalytic functions of protein kinases. Many noncatalytic 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 noncatalytic kinase activity: as allosteric modulators; protein-based switches; scaffolds for complex assembly; and as competitive inhibitors in signaling pathways. In common, these noncatalytic 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 noncatalytic protein kinase function in health and disease.

Automated summary

Protein kinases are known for their catalytic functions in cellular signaling, but recent research has shown that they also have noncatalytic roles. These noncatalytic activities, such as allosteric modulation and scaffolding, highlight the versatility of protein kinases as protein-protein interaction modules. Despite the challenges, targeting the noncatalytic functions of protein kinases with small molecules has significant potential in health and disease.