G Protein-coupled and Membrane Tyrosine Kinase Receptor Relationships Yield Therapeutic Opportunities

Leonard Girnita, Joseph AMJL Janssen, Terry J Smith
Endocrine Reviews, First published online July 4, 2025, bnaf019
https://doi.org/10.1210/endrev/bnaf019

Abstract

The aim of this review is to describe the complex evolutionary processes that have integrated signaling cascades associated with 2 structurally and mechanistically dissimilar receptor families: G protein-coupled receptors (GPCRs) and membrane-spanning tyrosine kinase receptors (RTKs). Precision medicine, employing advanced personalized therapeutic strategies, requires better understanding of multiple mechanisms governing both normal and pathological cell regulation. The functional overlap of GPCRs and RTKs exhibits complex interactions. GPCRs canonically activate signaling through their interactions with G proteins; however, they can also initiate G protein-independent signaling through interactions with β-arrestin 1/2. In contrast to the GPCRs, RTK canonical signaling is initiated with ligand-dependent receptor kinase-mediated phosphorylation of specific intrinsic tyrosine substrates. This, in turn, activates multiple intracellular pathways. Despite these distinguishing characteristics, GPCRs and RTKs might have a common evolutionary origin. This shared ancestry potentially explains why GPCRs and RTKs can behave as functional RTK/GPCR hybrids by “borrowing” from each other's signaling toolbox. Intermingling of these cell surface receptors can result in noncanonical receptor transactivation/inactivation, trafficking, and signaling. Several mechanisms for heterogeneous receptor crosstalk have been proposed, including receptor protein/protein interactions and sharing docking, scaffolding, and downstream effectors. Recent identification of these signaling complexities has revealed unanticipated feedback loops and patterns of downstream target gene activation. In sum, recognizing these biological complexities should facilitate novel approaches to high-specificity therapeutic targeting.

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