Blurring Boundaries: Receptor Tyrosine Kinases as functional G Protein-Coupled Receptors

International Review of Cell and Molecular Biology
Caitrin CruddenLeonard Girnita

Abstract

Receptor tyrosine kinases (RTKs) such as the insulin-like growth factor type 1 receptor (IGF-1R) control important biological activities as well as being involved in pathological processes. Due to their supportive nature in many human cancers they have long been considered attractive therapeutic targets. However, lessons learnt from early targeting trials highlight that a simple "active versus inactive" state model with classical kinase-only signaling is overly simplistic and does not describe reality. A vast amount of evidence exists disproving this model and hence provides a rational explanation for failure of many targeting agents designed under such a paradigm. In addition, substantial evidence exists that the IGF-1R and other RTKs make direct use of the G protein-coupled receptor (GPCR) components G proteins, GRKs, and β-arrestins, outside of their traditional receptor family frame. In this chapter we review the evidence that RTKs can undertake a wide range of active conformations, capable of distinct downstream signal cascades and propose an RTK/GPCR functional hybrid model, while discussing the implications of such an update on therapeutic drug development pipelines.

Citations

Oct 12, 2019·Cells·Caitrin CruddenLeonard Girnita
Mar 7, 2019·Frontiers in Pharmacology·Anna Bagnato, Laura Rosanò
May 31, 2019·Oncoimmunology·Sarah LévesqueGuido Kroemer
May 28, 2020·Science Signaling·Caitrin Crudden, Leonard Girnita
Jan 11, 2021·Journal of Experimental & Clinical Cancer Research : CR·Piera TocciAnna Bagnato
Sep 3, 2020·Growth Hormone & IGF Research : Official Journal of the Growth Hormone Research Society and the International IGF Research Society·Nasima BanoMohd Jamal Dar
Dec 12, 2021·Laboratory Investigation; a Journal of Technical Methods and Pathology·Nitin K AgarwalRalf Landgraf

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