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Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins

Dana S Neel1,2, David V Allegakoen1,2, Victor Olivas1,2

  • 1Department of Medicine, University of California at San Francisco, San Francisco, California.

Cancer Research
|December 13, 2018
PubMed

Insights

Receptor tyrosine kinase (RTK) fusions drive cancer. Distinct N-terminal partners alter ROS1 fusion protein location, affecting MAPK signaling and tumor aggression. Endosomal localization enhances oncogenic activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Chromosomal rearrangements of receptor tyrosine kinases (RTK) are key oncogenic drivers in human cancers.
  • RTK fusion oncoproteins typically consist of the kinase domain fused to a non-kinase N-terminal partner.
  • The role of these N-terminal partners in RTK fusion oncoprotein function is largely unknown.

Purpose of the Study:

  • To investigate how N-terminal fusion partners influence the subcellular localization and signaling of ROS1 receptor tyrosine kinase (RTK) fusion oncoproteins.
  • To determine the impact of differential subcellular localization on the oncogenic properties and MAPK pathway activation of ROS1 fusions.
  • To elucidate the clinical relevance of N-terminal partner-mediated regulation of RTK fusion oncoprotein activity.

Main Methods:

  • Generated and characterized distinct ROS1 fusion oncoproteins (SDC4-ROS1, SLC34A2-ROS1, CD74-ROS1 variants).
  • Utilized cell-based assays to assess subcellular localization (endosomes, ER) and MAPK pathway activation.
  • Performed functional studies to correlate subcellular localization with oncogenic potential and tumor aggressiveness.

Main Results:

  • N-terminal fusion partners dictated differential subcellular localization of ROS1 oncoproteins.
  • ROS1 fusions on endosomes (SDC4-ROS1, SLC34A2-ROS1) robustly activated MAPK signaling.
  • CD74-ROS1 variants in the endoplasmic reticulum (ER) showed impaired MAPK activation, which was restored upon forced relocalization to endosomes.
  • Enhanced MAPK activation correlated with increased tumor aggressiveness.

Conclusions:

  • The N-terminal fusion partner is a critical determinant of subcellular localization for ROS1 RTK fusion oncoproteins.
  • Differential subcellular localization modulates MAPK pathway activation and oncogenic output.
  • Endosomal localization confers stronger MAPK signaling and promotes more aggressive tumor formation, highlighting a novel mechanism of oncogenic regulation in RTK fusions.

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