Black Sheep: Pseudokinases Bucking the Trend to Reveal Non-Catalytic Kinase Functions

Pseudokinases are the catalytically-dead counterparts of protein kinases and, over the past 20 years, have increasingly garnered attention as crucial signaling entities-comprehensively dispelling the possibility that they are merely evolutionary remnants or cellular passengers. The field has been framed by a sequence-based definition of a pseudokinase, where the absence of one or more of the three critical catalytic residues required for phosphoryl transfer in conventional protein kinases has allowed their classification. As a result, pseudokinases have been defined by their dissimilarity to active kinases, meaning they are the outcasts or black sheep of the kinome. Pseudokinases are prevalent in nature, accounting for 10% or more of the kinase complement throughout phyla, and have been reported to mediate diverse functions in controlling the activities of other enzymes allosterically, mediating signaling complex assembly, serving as conformational switches and as negative regulators of signaling flux. Here, we review our current understanding of the varied pseudokinase functions as a window toward understanding non-catalytic functions of conventional protein kinases, the challenges associated with defining pseudokinases-especially in cases where cryptic catalytic activities have been reported-and the emergence of pseudokinases as pharmacological targets.