The RTK Interactome: Overview and Perspective on RTK Heterointeractions

Abstract

Receptor tyrosine kinases (RTKs) play important roles in cell growth, motility, differentiation, and survival. These single-pass membrane proteins are grouped into subfamilies based on the similarity of their extracellular domains. They are generally thought to be activated by ligand binding, which promotes homodimerization and then autophosphorylation in trans. However, RTK interactions are more complicated, as RTKs can interact in the absence of ligand and heterodimerize within and across subfamilies. Here, we review the known cross-subfamily RTK hetero-interactions and their possible biological implications, as well as the methodologies which have been used to study them. Moreover, we demonstrate how thermodynamic models can be used to study RTKs and to explain many of the complicated biological effects which have been described in the literature. Finally, we discuss the concept of the RTK interactome: a putative, extensive network of interactions between the RTKs. This RTK interactome can produce unique signaling outputs; can amplify, inhibit, and modify signaling; and can allow for signaling backups. The existence of the RTK interactome could provide an explanation for the irreproducibility of experimental data from different studies and for the failure of some RTK inhibitors to produce the desired therapeutic effects. We argue that a deeper knowledge of RTK interactome thermodynamics can lead to a better understanding of fundamental RTK signaling processes in health and disease. We further argue that there is a need for quantitative, thermodynamic studies that probe the strengths of the interactions between RTKs and their ligands and between different RTKs.

Analysis of transient membrane protein interactions by single-molecule diffusional mobility shift assay

“…While mutations or alterations in downstream effectors are considered the pertinent mechanisms of drug resistance, interactions between receptors, or heterointeractions, are also known causes of resistance 45 . Since heterointeractions between EGFR and other RTKs play an essential role in cancers, many papers have tried to decode these heterointeractions.…”

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

“…This homology is not restricted to EphAs but includes the related EphB family, allowing interclass EphA-EphB clusters [53]. Heterodimerization between EphAs and other RTKs members has also been observed (For review see [54]). Through intracellular domain interactions, FGF receptors can for instance dimerize with EphA4 and drive its activation [55].…”

A tyrosine kinase protein interaction map reveals targetable EGFR network oncogenesis in lung cancer

“…Coverage of tyrosine kinases using such experimental approaches has been minimal and is largely biased towards a small number of tyrosine kinases that are most intensely studied. Physical interactions are often also co-functional (Bandyopadhyay et al, 2010) and network maps can provide insights into associations with distinct cellular complexes (Stuart et al, 2006;James et al, 2009), unexpected cellular localizations (Ni et al, 2001;Carpenter, 2003;Carpenter and Liao, 2013) and transactivation partners (Paul and Hristova, 2019).…”