Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins

Dana S. Neel, David V. Allegakoen, Victor Olivas, Manasi K. Mayekar, Golzar Hemmati, Nilanjana Chatterjee, Collin M. Blakely, Caroline E. McCoach, Julia K. Rotow, Anh Le, Niki Karachaliou, Rafael Rosell, Jonathan Riess, Robert Nichols, Robert C. Doebele, Trever G. Bivona

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)546-556
Number of pages11
JournalCancer Research
Issue number3
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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