Location, location, location: Protein kinase nanoclustering for optimised signalling output

Abstract

Protein kinases (PKs) are proteins at the core of cellular signalling and are thereby responsible for most cellular physiological processes and their regulations. As for all intracellular proteins, PKs are subjected to Brownian thermal energy that tends to homogenise their distribution throughout the volume of the cell. To access their substrates and perform their critical functions, PK localisation is therefore tightly regulated in space and time, relying upon a range of clustering mechanisms. These include post-translational modifications, protein–protein and protein–lipid interactions, as well as liquid–liquid phase separation, allowing spatial restriction and ultimately regulating access to their substrates. In this review, we will focus on key mechanisms mediating PK nanoclustering in physiological and pathophysiological processes. We propose that PK nanoclusters act as a cellular quantal unit of signalling output capable of integration and regulation in space and time. We will specifically outline the various super-resolution microscopy approaches currently used to elucidate the composition and mechanisms driving PK nanoscale clustering and explore the pathological consequences of altered kinase clustering in the context of neurodegenerative disorders, inflammation, and cancer.

Spatiotemporal regulation of the hepatocyte growth factor receptor MET activity by sorting nexins 1/2 in HCT116 colorectal cancer cells

“…It is now evident that the endosomal system also serves as a pivotal site for signal transduction. Activated RTKs continue to transmit signal from endosomes, yielding responses different from those initiated at the plasma membrane, thereby eliciting distinct physiological responses [ 5 , 6 ]. Notably, this endosomal signaling extends beyond RTKs and has also been shown for G-protein coupled receptors [ 7 , 8 ].…”

Allosteric regulation of kinase activity

“…For example, Venkat et al report on the role of intrinsically disordered regions in a process called isoform-specific ‘supercharging’ in the DCLK family of kinases ( Venkat et al, 2023 ), and Tariq et al highlight the role of disorder and phase separation in controlling the phosphorylation events that organize the circadian clock in a fungal system ( Tariq et al, 2024 ). Elsewhere, in a review article, Gormal et al discuss the mechanisms responsible for kinase clustering, and how this phenomenon can drive various pathologies ( Gormal et al, 2023 ). In all these examples, the lack of a stable tertiary structure presents a major challenge to researchers trying to understand the allosteric mechanisms responsible.…”