RAS at the Golgi antagonizes malignant transformation through PTPRκ-mediated inhibition of ERK activation

被引：18

作者：

Casar, Berta ^{[1
,2
]}

Badrock, Andrew P. ^{[3
]}

Jimenez, Inaki ^{[1
]}

Arozarena, Imanol ^{[1
,7
]}

Colon-Bolea, Paula ^{[1
]}

Francisco Lorenzo-Martin, L. ^{[2
,4
,5
]}

Barinaga-Rementeria, Irene ^{[3
]}

Barriuso, Jorge ^{[3
]}

Cappitelli, Vincenzo

Donoghue, Daniel J. ^{[6
]}

Bustelo, Xose R. ^{[2
,4
,5
]}

Hurlstone, Adam ^{[3
]}

Crespo, Piero ^{[1
,2
]}

机构：

[1] Univ Cantabria, CSIC, Inst Biomed & Biotecnol Cantabria IBBTEC, Santander 39011, Spain

[2] Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain

[3] Univ Manchester, Fac Biol Med & Hlth, Sch Med Sci, Div Canc Studies, Manchester M13 9PL, Lancs, England

[4] Univ Salamanca, Ctr Invest Canc, CSIC, Salamanca 37007, Spain

[5] Univ Salamanca, CSIC, Inst Biol Mol & Celular Canc, Salamanca 37007, Spain

[6] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA

[7] Navarrabiomed FMS IDISNA, Navarra 31008, Spain

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

欧洲研究理事会;

关键词：

PLASMA-MEMBRANE; H-RAS; SIGNALING PATHWAY; TYROSINE PHOSPHORYLATION; ENDOPLASMIC-RETICULUM; CELL-PROLIFERATION; INDUCED APOPTOSIS; EXCHANGE FACTORS; TARGET GENE; N-RAS;

D O I：

10.1038/s41467-018-05941-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

RAS GTPases are frequently mutated in human cancer. H- and NRAS isoforms are distributed over both plasma-membrane and endomembranes, including the Golgi complex, but how this organizational context contributes to cellular transformation is unknown. Here we show that RAS at the Golgi is selectively activated by apoptogenic stimuli and antagonizes cell survival by suppressing ERK activity through the induction of PTPR kappa, which targets CRAF for dephosphorylation. Consistently, in contrast to what occurs at the plasma-membrane, RAS at the Golgi cannot induce melanoma in zebrafish. Inactivation of PTPR kappa, which occurs frequently in human melanoma, often coincident with TP53 inactivation, accelerates RAS-ERK pathway-driven melanomagenesis in zebrafish. Likewise, tp53 disruption in zebrafish facilitates oncogenesis driven by RAS from the Golgi complex. Thus, RAS oncogenic potential is strictly dependent on its sublocalization, with Golgi complex-located RAS antagonizing tumor development.

引用

页数：17

共 67 条

[21] Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway [J].