ZFIN ID: ZDB-PUB-180907-4
RAS at the Golgi antagonizes malignant transformation through PTPRκ-mediated inhibition of ERK activation
Casar, B., Badrock, A.P., Jiménez, I., Arozarena, I., Colón-Bolea, P., Lorenzo-Martín, L.F., Barinaga-Rementería, I., Barriuso, J., Cappitelli, V., Donoghue, D.J., Bustelo, X.R., Hurlstone, A., Crespo, P.
Date: 2018
Source: Nature communications   9: 3595 (Journal)
Registered Authors: Badrock, Andrew P., Hurlstone, Adam
Keywords: none
MeSH Terms:
  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic/pathology*
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • Golgi Apparatus/metabolism*
  • Humans
  • MAP Kinase Signaling System/physiology
  • Melanoma/pathology*
  • Mice
  • NIH 3T3 Cells
  • RNA, Small Interfering/metabolism
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism*
  • Zebrafish
  • Zebrafish Proteins/metabolism
  • ras Proteins/metabolism*
PubMed: 30185827 Full text @ Nat. Commun.
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ABSTRACT
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 PTPRκ, 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 PTPRκ, 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.
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