1. Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins.
- Author
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Neel DS, Allegakoen DV, Olivas V, Mayekar MK, Hemmati G, Chatterjee N, Blakely CM, McCoach CE, Rotow JK, Le A, Karachaliou N, Rosell R, Riess JW, Nichols R, Doebele RC, and Bivona TG
- 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
- 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., (©2018 American Association for Cancer Research.)
- Published
- 2019
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