Fig. 11

Diagram illustrating the molecular processes involved in GPCR desensitization via transactivation of EGFR. The content presented in this diagram aligns with the newly proposed concept of the GPCR desensitization hypothesis, as described in recent literature [11]. In the resting state, Mdm2 relocates to the cytoplasm, where it continually adds ubiquitin molecules to arrestins. When desensitization occurs, the Gα and Gβγ subunits detach from the receptor. Concurrently, the receptor triggers signaling through Src, activating PDK1 and subsequently Akt via phosphorylation at S241 and T308, respectively. Active Akt then interacts with USP33 to enhance its enzyme activity, leading to the removal of ubiquitin molecules from arrestins. Once deubiquitinated, arrestins bind with Gβγ and migrate to the nucleus through the importin complex, effectively sequestering Gβγ from both the receptor and Gα. This action diminishes the efficiency of receptor signaling, resulting in desensitization. In this study, we add that a cascade of regulatory events involved in this innovative GPCR desensitization process is initiated through transactivation between GPCR and EGFR