The PEAK family of pseudokinases, their role in cell signalling and cancer

The study of pseudokinases has uncovered that catalysis-independent functions play a critical role in cell signalling regulation. However, how pseudokinases dynamically assemble and regulate oncogenic signalling pathways remains, in most cases, unclear due to a limited knowledge of the structural determinants that are critical for their functions. Here, we review the recent progress made to unravel the role of the PEAK family of pseudokinases, which comprises SgK269, SgK223 and the recently identified PEAK3, in assembling specific oncogenic signalling pathways that contribute to the progression of several aggressive cancers. We focus on recent structural advances revealing that SgK269 and SgK223 can homo- and heteroassociate via a unique dimerisation domain, comprising conserved regulatory helices directly surrounding the pseudokinase domain, which is also conserved in PEAK3. We also highlight a potential oligomerisation mechanism driven by the pseudokinase domain. While it is likely that homo- or heterodimerisation and oligomerisation mechanisms contribute to the assembly of complex signalling hubs and provide a means to spatially and temporally modulate and diversify signalling outputs, the exact role that these oncogenic scaffolds play in regulating cell migration, invasion and morphology remains unclear. Here, we attempt to link their structural characteristics to their cellular functions by providing a thorough analysis of the signalling transduction pathways they are known to modulate.