2. GPCR signaling in cancer
2.1 Classical GPCR signaling
pathways
Activation of GPCRs represents a pivotal molecular event in cellular
signaling cascades. Upon ligand binding, these receptors undergo
conformational changes, which catalyze the dissociation of GDP from the
G protein Gα subunit, followed by the binding of GTP to
Gα and the subsequent separation of Gαfrom the Gβ/γ subunits (Pierce, Premont, & Lefkowitz,
2002). This separation allows Gα to modulate downstream
effector molecules, such as adenylyl cyclase (AC) or phospholipase C
(PLC), initiating a diverse array of intracellular responses that lead
to changes in cell proliferation, migration, or cell survival (Figure 1)
(Kamps & Coffman, 2005). Gαs / Gαi can
either upregulate or downregulate AC activity, modulating cyclic AMP
(cAMP) production and subsequent activation of protein kinase A (PKA).
PKA is a key intracellular mediator that induces the phosphorylation of
target proteins. Gαq induces PLC activation, leading to
intracellular calcium mobilization and diverse responses.
Gα12/13, while less understood, has emerged as a key
player in cell migration, cytoskeletal dynamics, and oncogenic
transformation (Rasheed et al. , 2022).. Following GPCR
activation, G protein-coupled receptor kinases (GRKs) play a crucial
role in the phosphorylation of GPCRs and subsequent recruitment of
β-arrestins. These protein have been shown to cause distinct cellular
responses, including receptor desensitization, internalization that
prevent further G protein coupling, but also activation of signaling
cascades such as the mitogen-activated protein kinase (MAPK) pathway (S.
K. Shenoy & Lefkowitz, 2005) (Gurevich & Gurevich, 2019). Hence,
together G proteins and β-arrestins orchestrate a finely tuned cellular
response upon GPCR activation by extracellular stimuli.