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.