Beyond Receptor-Proximal Uncoupling: EGFR-PKC Signaling and Arrestin Deubiquitination-Coupled Nuclear Trafficking in GPCR Signaling Regulation

G protein-coupled receptors (GPCRs) constitute the largest family of cell-surface signaling proteins and major therapeutic targets.Their function is critically shaped by desensitization, the attenuation of receptor responsiveness during sustained or repeated stimulation.The canonical model, established in systems such as rhodopsin and the ₂-adrenergic receptor, emphasizes GRKmediated receptor phosphorylation, arrestin recruitment, and steric inhibition of G-protein coupling, resulting in rapid and largely reversible receptor desensitization.Accumulating evidence, however, indicates that GPCR adaptation can extend beyond this receptor-proximal mechanism.Here, I propose a Two-Level Framework that incorporates an EGFR-dependent adaptive program following sustained activation of selected GPCRs.EGFR serves as an upstream integration hub linking two complementary pathways: a PKC-dependent proximal pathway that mediates receptor-level desensitization, and a Src-PDK1-Akt-USP33 pathway proposed to promote arrestin deubiquitination and subsequent nuclear translocation of arrestin-G complexes.This translocation may reduce membrane-associated G availability, thereby contributing to persistent attenuation of receptor signaling, while also influencing nuclear transcriptional activity.The persistent component is revealed by washout-rechallenge paradigms, in which signaling remains impaired despite apparent receptor recovery.Thus, Level II represents an additional layer of GPCR adaptation in which receptor desensitization is accompanied by longer-lasting remodeling of intracellular signaling capacity.Although derived primarily from D2-like and  2 -adrenergic receptor systems, this framework may apply more broadly to GPCRs capable of transactivating EGFR or related receptor tyrosine kinases, providing a broader view of desensitization that integrates receptor-level regulation with network-level adaptation.