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Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins.
- Source :
-
Cancer research [Cancer Res] 2019 Feb 01; Vol. 79 (3), pp. 546-556. Date of Electronic Publication: 2018 Dec 11. - Publication Year :
- 2019
-
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.<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Adenocarcinoma of Lung enzymology
Adenocarcinoma of Lung genetics
Adenocarcinoma of Lung pathology
Animals
Antigens, CD genetics
Antigens, CD metabolism
Endosomes metabolism
HEK293 Cells
Humans
Lung Neoplasms genetics
Lung Neoplasms pathology
MAP Kinase Signaling System
Mice
Mice, Inbred NOD
Mice, SCID
NIH 3T3 Cells
Oncogene Proteins, Fusion genetics
Protein-Tyrosine Kinases genetics
Proto-Oncogene Proteins genetics
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
Adenocarcinoma of Lung metabolism
Lung Neoplasms metabolism
Oncogene Proteins, Fusion metabolism
Protein-Tyrosine Kinases metabolism
Proto-Oncogene Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 79
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 30538120
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-18-1492