Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins
Por:
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
Publicada:
1 feb 2019
Ahead of Print:
11 dic 2018
Resumen:
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.
Filiaciones:
Neel, DS:
Univ Calif San Francisco, Dept Med, San Francisco, CA USA
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 600 16th St,N212D, San Francisco, CA 94158 USA
Allegakoen, DV:
Univ Calif San Francisco, Dept Med, San Francisco, CA USA
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 600 16th St,N212D, San Francisco, CA 94158 USA
Olivas, V:
Univ Calif San Francisco, Dept Med, San Francisco, CA USA
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 600 16th St,N212D, San Francisco, CA 94158 USA
Mayekar, MK:
Univ Calif San Francisco, Dept Med, San Francisco, CA USA
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 600 16th St,N212D, San Francisco, CA 94158 USA
Hemmati, G:
Univ Calif San Francisco, Dept Med, San Francisco, CA USA
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 600 16th St,N212D, San Francisco, CA 94158 USA
Chatterjee, N:
Univ Calif San Francisco, Dept Med, San Francisco, CA USA
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 600 16th St,N212D, San Francisco, CA 94158 USA
Blakely, CM:
Univ Calif San Francisco, Dept Med, San Francisco, CA USA
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 600 16th St,N212D, San Francisco, CA 94158 USA
McCoach, CE:
Univ Calif San Francisco, Dept Med, San Francisco, CA USA
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 600 16th St,N212D, San Francisco, CA 94158 USA
Rotow, JK:
Univ Calif San Francisco, Dept Med, San Francisco, CA USA
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 600 16th St,N212D, San Francisco, CA 94158 USA
Le, A:
Univ Colorado, Dept Med, Anschutz Med Campus, Denver, CO USA
Karachaliou, N:
Hosp Germans Trias i Pujol Badalona, Catalan Inst Oncol, Canc Biol & Precis Med Program, Barcelona, Spain
:
Hosp Germans Trias i Pujol Badalona, Catalan Inst Oncol, Canc Biol & Precis Med Program, Barcelona, Spain
Riess, JW:
Univ Calif Davis, Sch Med, Sacramento, CA 95817 USA
Comprehens Canc Ctr, Sacramento, CA USA
Nichols, R:
Revolut Med, Redwood City, CA USA
Doebele, RC:
Univ Colorado, Dept Med, Anschutz Med Campus, Denver, CO USA
Bivona, TG:
Univ Calif San Francisco, Dept Med, San Francisco, CA USA
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 600 16th St,N212D, San Francisco, CA 94158 USA
Bronze, Green Accepted
|