The secret life of kinases: insights into non‐catalytic functions from pseudokinases

Abstract

While protein kinases are best understood for their phosphoryl transfer enzymatic activities, recent mechanistic studies have led to recognition of non‐catalytic functions in cell signaling. Studies of pseudokinases ‐ the catalytically‐impaired or dead cousins of conventional protein kinases ‐ have been instrumental in shining light on the vast, varied and ever‐expanding repertoire of mechanisms by which kinase‐like domains can mediate protein interactions to modulate cellular signaling.Although best characterized as allosteric regulators of conventional, active protein kinases, our work and that of others suggests more broadly that pseudokinase domains are important protein interaction modules that can function as molecular switches, scaffolds and adaptors in cell signaling pathways. Here, I will describe how our work has attributed these functions to the pseudokinase, Mixed lineage kinase domain‐like (MLKL). Overall, these studies suggest how conventional protein kinases could moonlight as protein interaction modules, scaffolds or molecular switches to complement their better‐understood catalytic roles.Support or Funding InformationNational Health and Medical Research Council of Australia (fellowship 1105754, grants 1057905, 1067289, infrastructure 9000220) and Victorian Government Operational Infrastructure Support.