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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

1
Department of Medicine, University of California at San Francisco, San Francisco, California.
2
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
3
Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, Colorado.
4
Cancer Biology and Precision Medicine Program Catalan Institute of Oncology Hospital Germans Trias i Pujol Badalona, Barcelona, Spain.
5
University of California Davis School of Medicine, Sacramento, California.
6
Comprehensive Cancer Center, Sacramento, California.
7
Revolution Medicines, Redwood City, California.
8
Department of Medicine, University of California at San Francisco, San Francisco, California. trever.bivona@ucsf.edu.

Abstract

: 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.

PMID:
30538120
PMCID:
PMC6359944
[Available on 2020-02-01]
DOI:
10.1158/0008-5472.CAN-18-1492

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