PUBLICATION

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

Authors
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.
ID
ZDB-PUB-180907-4
Date
2018
Source
Nature communications   9: 3595 (Journal)
Registered Authors
Badrock, Andrew P., Hurlstone, Adam
Keywords
none
MeSH Terms
  • Humans
  • RNA, Small Interfering/metabolism
  • NIH 3T3 Cells
  • MAP Kinase Signaling System/physiology
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism*
  • Golgi Apparatus/metabolism*
  • Melanoma/pathology*
  • Gene Knockdown Techniques
  • ras Proteins/metabolism*
  • Cell Line, Tumor
  • Animals
  • Cell Transformation, Neoplastic/pathology*
  • Disease Models, Animal
  • Zebrafish
  • Mice
  • Zebrafish Proteins/metabolism
(all 17)
PubMed
30185827 Full text @ Nat. Commun.
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.
Genes / Markers
Figures
Figure Gallery (4 images)
Show all Figures
Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
ptprkptprkumc14/umc14standard conditionsShieldRTPCR
ptprkptprkumc15/umc15standard conditionsShieldRTPCR
ptprkWTstandard conditionsShieldRTPCR
1 - 3 of 3
Show
Phenotype
Fish Conditions Stage Phenotype Figure
ptprkumc14/umc14standard conditionsShield
ptprkumc14/umc14standard conditionsAdult
ptprkumc14/umc14standard conditionsAdult
ptprkumc14/umc14standard conditionsAdult
ptprkumc15/umc15standard conditionsShield
ptprkumc15/umc15standard conditionsAdult
ptprkumc15/umc15standard conditionsAdult
ptprkumc15/umc15standard conditionsAdult
1 - 8 of 8
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
umc14
    		Small Deletion
    umc15
      		Small Deletion
      w2
        		Point Mutation
        zdf1
          		Point Mutation
          1 - 4 of 4
          Show
          Human Disease / Model
          Human Disease Fish Conditions Evidence
          melanomaTAS
          1 - 1 of 1
          Show
          Sequence Targeting Reagents
          Target Reagent Reagent Type
          ptprkCRISPR1-ptprkCRISPR
          1 - 1 of 1
          Show
          Fish
          Fish
          mitfaw2/w2
          mitfaw2/w2; ptprkumc14/umc14
          mitfaw2/w2; ptprkumc15/umc15
          mitfaw2/w2; tp53zdf1/zdf1
          ptprkumc14/umc14
          ptprkumc15/umc15
          WT
          1 - 7 of 7
          Show
          Antibodies
          No data available
          Orthology
          No data available
          Engineered Foreign Genes
          No data available
          Mapping
          No data available
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          Citation
          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. (2018) RAS at the Golgi antagonizes malignant transformation through PTPRκ-mediated inhibition of ERK activation. Nature communications. 9:3595.