Fig. 2: The role of E3 ubiquitin ligases in RTK signalling in GB.

RTKs are transmembrane receptors containing extracellular, transmembrane and intracellular portions. The extracellular domain interfaces with the extracellular milieu allowing expressing cells to react and adapt to extracellular signals. Upon binding their cognate ligands, RTKs undergo autophosphorylation leading to downstream signalling [156]. In this way, RTKs transduce extracellular cues as signals into a cell. EGF signalling is a prototypical example of altered RTK signalling in GB. Activation of the receptor leads to phosphorylation of c-terminal residue tyrosines, facilitating the docking of Src homology (SH) domain-containing proteins and activation of several pathways, including the MAPK pathway, signal transducers and activators of transcription (STAT) signalling and Src-dependent phosphoinositide 3-kinase (PI3K)/Akt signalling [157]. At the membrane, E3s such as c-CBL can decrease oncogenic signalling by promoting EGFR ubiquitylation and turnover. RTK signalling converges on several pathways including the phosphoinositide 3-kinase (PI3K)/Akt pathway. Activation-dependent phosphorylation of RTKs (such as EGFR) facilitates the binding of class 1a PI3K via SH2 domains. This leads to the activation of PI3K and subsequent phosphorylation of phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 4,5-triphosphate (PIP₃) [158]. Via pleckstrin homology (PH) domains, Akt binds PIP₃ where it is phosphorylated by phosphoinositide-dependent protein kinase-1 (PDK-1). An important negative regulator of this pathway is the phosphatase and tensin homologue (PTEN), a protein whose gene is mutated/deleted in 41% of GB cases. Akt signalling can also be modulated via negative feedback loops with phosphatases including PH domain leucine-rich repeat protein phosphatase (PHLPP) [159, 160]. The MAPK pathway is an important downstream signalling pathway activated by RTKs. As  one of the most commonly mutated pathways in human cancer, it translates  extracellular signals into cellular phenotypes such as proliferation, differentiation, migration and invasion [161]. Following RTK activation, son of sevenless (Sos) is recruited to the plasma membrane via interaction with Grb2. Sos is a guanine nucleotide exchange factor (GEF) which promotes the activation of membrane-bound RAS via binding of guanosine triphosphate (GTP) with Ras. Active Ras can then promote multiple oncogenic cellular responses. In contrast, GTPase-activating proteins (GAPs) accelerate Ras-mediated GTP hydrolysis and act as negative regulators of Ras signalling and are therefore tumour suppressors [162]. Red icons represent E3 ligases and their functions as observed in GB models. Where specific substrates are yet to be identified, E3 ligases appear as pink icons.