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Density Gradient Ultracentrifugation for Investigating Endocytic Recycling in Mammalian Cells
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Published on: June 30, 2021

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Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs

Michael P Smith1, Harriet R Ferguson1, Jennifer Ferguson1

  • 1Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, Manchester, UK.

The EMBO Journal
|June 4, 2021
PubMed

Insights

Recycling endosomes coordinate fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) signaling. This reciprocal priming influences breast cancer cell proliferation and may offer new therapeutic targets.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Receptor tyrosine kinases (RTKs) signaling integration is vital for cellular homeostasis and cancer development.
  • Mechanisms regulating RTK signaling integration and the role of receptor endocytosis remain unclear.
  • Fibroblast growth factor receptors (FGFRs) and epidermal growth factor receptor (EGFR) are key RTKs implicated in breast cancer.

Purpose of the Study:

  • To elucidate the role of receptor endocytic fate in regulating signaling integration.
  • To investigate the interplay between distinct RTKs, specifically FGFRs and EGFR, in breast cancer cells.
  • To identify novel mechanisms of signaling integration at recycling endosomes.

Main Methods:

  • Quantitative phosphoproteomics to map signaling networks.
  • Targeted assays to analyze receptor trafficking and function.
  • Study focused on recycling-dependent fibroblast growth factor (FGF) signaling in breast cancer models.

Main Results:

  • Discovered reciprocal priming between FGFRs and EGFR coordinated at recycling endosomes.
  • FGFR activation induces EGFR phosphorylation at threonine 693, altering trafficking and priming proliferation.
  • FGFR signaling reciprocally primes EGF-mediated outputs via EGFR threonine 693 phosphorylation.

Conclusions:

  • Recycling endosomes act as a novel signaling integration hub orchestrating RTK crosstalk.
  • Reciprocal priming between FGFRs and EGFR regulates breast cancer cell proliferation.
  • Targeting this reciprocal priming mechanism may offer improved personalized cancer therapies.
Keywords:
fibroblast growth factor receptorquantitative phosphoproteomicsreceptor tyrosine kinasessignallingtrafficking

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