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

Caitrin Crudden1, Takashi Shibano1, Dawei Song1

  • 1Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

International Review of Cell and Molecular Biology
|May 20, 2018
PubMed

Insights

Receptor tyrosine kinases (RTKs) like the insulin-like growth factor type 1 receptor (IGF-1R) have complex signaling pathways. New models suggest RTKs interact with G protein-coupled receptor (GPCR) components, impacting cancer therapy development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Receptor tyrosine kinases (RTKs), including the insulin-like growth factor type 1 receptor (IGF-1R), are crucial in biological processes and implicated in cancer.
  • Traditional therapeutic strategies targeting RTKs have faced challenges due to an oversimplified view of their signaling mechanisms.

Purpose of the Study:

  • To review evidence supporting a more complex signaling model for RTKs.
  • To propose a novel functional hybrid model integrating RTK and G protein-coupled receptor (GPCR) components.
  • To discuss the implications of this updated model for therapeutic drug development.

Main Methods:

  • Literature review of existing evidence on RTK and GPCR interactions.
  • Analysis of signaling pathways involving RTKs, G proteins, GRKs, and β-arrestins.
  • Conceptual modeling of RTK/GPCR functional interactions.

Main Results:

  • Evidence indicates RTKs utilize G protein-coupled receptor (GPCR) machinery (G proteins, GRKs, β-arrestins).
  • RTKs can adopt diverse active conformations, leading to distinct downstream signaling cascades.
  • A functional hybrid RTK/GPCR model offers a more accurate representation of RTK signaling.

Conclusions:

  • The classical kinase-only signaling model for RTKs is insufficient.
  • RTKs function as hybrid receptors, interacting with GPCR signaling elements.
  • This revised understanding necessitates a re-evaluation of therapeutic strategies targeting RTKs in diseases like cancer.
Keywords:
Beta-arrestinsBiased signalingCancerFunctional selectivityG proteinsGPCRGRKsIGF-1RRTKTargeted therapy

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