Send to

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

Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins.

Author information

Department of Medicine, University of California at San Francisco, San Francisco, California.
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, Colorado.
Cancer Biology and Precision Medicine Program Catalan Institute of Oncology Hospital Germans Trias i Pujol Badalona, Barcelona, Spain.
University of California Davis School of Medicine, Sacramento, California.
Comprehensive Cancer Center, Sacramento, California.
Revolution Medicines, Redwood City, California.
Department of Medicine, University of California at San Francisco, San Francisco, California.


: 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.

[Available on 2020-02-01]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center