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 journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)546-556
Number of pages11
JournalCancer Research
Volume79
Issue number3
DOIs
StatePublished - Feb 1 2019

Fingerprint

Oncogene Proteins
Protein Kinases
Receptor Protein-Tyrosine Kinases
Endosomes
Endoplasmic Reticulum
Neoplasms
Phosphotransferases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Neel, D. S., Allegakoen, D. V., Olivas, V., Mayekar, M. K., Hemmati, G., Chatterjee, N., ... Bivona, T. G. (2019). Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins. Cancer Research, 79(3), 546-556. https://doi.org/10.1158/0008-5472.CAN-18-1492

Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins. / 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; Nichols, Robert; Doebele, Robert C.; Bivona, Trever G.

In: Cancer Research, Vol. 79, No. 3, 01.02.2019, p. 546-556.

Research output: Contribution to journalArticle

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, J, Nichols, R, Doebele, RC & Bivona, TG 2019, 'Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins', Cancer Research, vol. 79, no. 3, pp. 546-556. https://doi.org/10.1158/0008-5472.CAN-18-1492
Neel DS, Allegakoen DV, Olivas V, Mayekar MK, Hemmati G, Chatterjee N et al. Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins. Cancer Research. 2019 Feb 1;79(3):546-556. https://doi.org/10.1158/0008-5472.CAN-18-1492
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 ; Nichols, Robert ; Doebele, Robert C. ; Bivona, Trever G. / Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins. In: Cancer Research. 2019 ; Vol. 79, No. 3. pp. 546-556.
@article{f463f70c98514657a3168a1e0b217953,
title = "Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins",
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.",
author = "Neel, {Dana S.} and Allegakoen, {David V.} and Victor Olivas and Mayekar, {Manasi K.} and Golzar Hemmati and Nilanjana Chatterjee and Blakely, {Collin M.} and McCoach, {Caroline E.} and Rotow, {Julia K.} and Anh Le and Niki Karachaliou and Rafael Rosell and Jonathan Riess and Robert Nichols and Doebele, {Robert C.} and Bivona, {Trever G.}",
year = "2019",
month = "2",
day = "1",
doi = "10.1158/0008-5472.CAN-18-1492",
language = "English (US)",
volume = "79",
pages = "546--556",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins

AU - Neel, Dana S.

AU - Allegakoen, David V.

AU - Olivas, Victor

AU - Mayekar, Manasi K.

AU - Hemmati, Golzar

AU - Chatterjee, Nilanjana

AU - Blakely, Collin M.

AU - McCoach, Caroline E.

AU - Rotow, Julia K.

AU - Le, Anh

AU - Karachaliou, Niki

AU - Rosell, Rafael

AU - Riess, Jonathan

AU - Nichols, Robert

AU - Doebele, Robert C.

AU - Bivona, Trever G.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85060915914&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060915914&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-18-1492

DO - 10.1158/0008-5472.CAN-18-1492

M3 - Article

C2 - 30538120

AN - SCOPUS:85060915914

VL - 79

SP - 546

EP - 556

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 3

ER -