Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins

Cancer Res. 2019 Feb 1;79(3):546-556. doi: 10.1158/0008-5472.CAN-18-1492. Epub 2018 Dec 11.


Chromosomal rearrangements involving receptor tyrosine kinases (RTK) are a clinically relevant oncogenic mechanism in human cancers. These chimeric oncoproteins often contain the C-terminal kinase domain of the RTK joined in cis to various N-terminal, nonkinase fusion partners. The functional role of the N-terminal fusion partner in RTK fusion oncoproteins is poorly understood. Here, we show that distinct N-terminal fusion partners drive differential subcellular localization, which imparts distinct cell signaling and oncogenic properties of different, clinically relevant ROS1 RTK fusion oncoproteins. SDC4-ROS1 and SLC34A2-ROS1 fusion oncoproteins resided on endosomes and activated the MAPK pathway. CD74-ROS1 variants that localized instead to the endoplasmic reticulum (ER) showed compromised activation of MAPK. Forced relocalization of CD74-ROS1 from the ER to endosomes restored MAPK signaling. ROS1 fusion oncoproteins that better activate MAPK formed more aggressive tumors. Thus, differential subcellular localization controlled by the N-terminal fusion partner regulates the oncogenic mechanisms and output of certain RTK fusion oncoproteins. SIGNIFICANCE: ROS1 fusion oncoproteins exhibit differential activation of MAPK signaling according to subcellular localization, with ROS1 fusions localized to endosomes, the strongest activators of MAPK signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / enzymology
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / metabolism*
  • Adenocarcinoma of Lung / pathology
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Endosomes / metabolism
  • HEK293 Cells
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • NIH 3T3 Cells
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Sialyltransferases / genetics
  • Sialyltransferases / metabolism
  • Sodium-Phosphate Cotransporter Proteins, Type IIb / genetics
  • Sodium-Phosphate Cotransporter Proteins, Type IIb / metabolism
  • Subcellular Fractions / metabolism
  • Syndecan-4 / genetics
  • Syndecan-4 / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • Antigens, CD
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • SDC4 protein, human
  • SLC34A2 protein, human
  • Sodium-Phosphate Cotransporter Proteins, Type IIb
  • Syndecan-4
  • Sialyltransferases
  • ST6GAL1 protein, human
  • Protein-Tyrosine Kinases
  • ROS1 protein, human
  • ras Proteins