Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 3; pp. 546 - 556
• Main Authors: Neel, Dana S, Allegakoen, David V, Olivas, Victor, Mayekar, Manasi K, Hemmati, Golzar, Chatterjee, Nilanjana, Blakely, Collin M, McCoach, Caroline E, Rotow, Julia K, Le, Anh, Karachaliou, Niki, Rosell, Rafael, Riess, Jonathan W, Nichols, Robert, Doebele, Robert C, Bivona, Trever G
• Format: Journal Article
• Language: English
• Published: United States 01-02-2019
• Subjects: 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; ras Proteins - genetics; ras 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
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-18-1492

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
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.