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 language | English (US) |
|---|---|
| Pages (from-to) | 546-556 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 79 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 1 2019 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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 journal › Article
}
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 -