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Identification of Kinase-substrate Pairs Using High Throughput Screening
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Phosphoproteome analysis of the MAPK pathway reveals previously undetected feedback mechanisms

Florian Gnad1, Sophia Doll2, Kyung Song3

  • 1Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, CA, USA.

Proteomics
|June 9, 2016
PubMed

Insights

This study deciphers the complex phosphorylation network of the RAS-RAF-MEK-ERK (MAPK) pathway in cancer. It identifies new feedback mechanisms and potential therapeutic targets by analyzing protein phosphorylation changes upon MEK or ERK inhibition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Proteomics

Background:

  • The RAS-RAF-MEK-ERK (MAPK) pathway is frequently altered in various cancers, with KRAS and BRAF being key mutated proteins.
  • Targeted therapies for MAPK pathway-driven cancers face challenges due to pathway complexity.
  • Understanding the intricate phosphorylation network is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the phosphorylation network of the MAPK pathway.
  • To identify previously undetected feedback loops and signaling nodes.
  • To discover novel therapeutic targets within the MAPK cascade.

Main Methods:

  • Utilized mass spectrometry to identify and quantify phosphorylation sites on proteins.
  • Measured phosphorylation site responses to MEK and ERK inhibition.
  • Integrated data with The Cancer Genome Atlas (TCGA) for clinical relevance.

Main Results:

  • Identified 2241 phosphorylation sites on 1020 proteins.
  • Revealed previously unknown feedback mechanisms involving upstream signaling nodes.
  • Highlighted frequently altered downstream phosphoproteins in cancer using TCGA data.

Conclusions:

  • The study provides a comprehensive map of MAPK pathway phosphorylation.
  • Identified novel potential therapeutic targets for MAPK-driven cancers.
  • The findings offer insights into resistance mechanisms and guide future therapeutic strategies.
Keywords:
Cell BiologyERKMAPKMEKMass spectrometryPhosphoproteomicsSignaling

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