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Spatial and Temporal Analysis of Active ERK in the C. elegans Germline
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RAS at the Golgi antagonizes malignant transformation through PTPRκ-mediated inhibition of ERK activation

Berta Casar1,2, Andrew P Badrock3, Iñaki Jiménez1

  • 1Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria, Santander, 39011, Spain.

Nature Communications
|September 7, 2018
PubMed

Insights

RAS GTPases at the Golgi complex antagonize cancer cell survival by suppressing the ERK pathway. Inactivation of PTPRκ or TP53 accelerates RAS-driven melanomagenesis, highlighting RAS sublocalization

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • RAS GTPases are frequently mutated in human cancers.
  • RAS isoforms, including H- and NRAS, localize to the plasma membrane and endomembranes, such as the Golgi complex.
  • The role of RAS localization within the Golgi complex in cellular transformation remains unclear.

Purpose of the Study:

  • To investigate the function of RAS at the Golgi complex in cellular transformation and cancer development.
  • To determine how Golgi-localized RAS influences cell survival pathways, specifically the ERK pathway.
  • To explore the interplay between RAS sublocalization, PTPRκ, TP53, and melanomagenesis.

Main Methods:

  • Utilized cell biology techniques to study RAS localization and activation at the Golgi complex.
  • Investigated the induction of PTPRκ by Golgi-localized RAS and its effect on CRAF dephosphorylation.
  • Employed zebrafish models to assess the oncogenic potential of RAS at different cellular compartments and the impact of PTPRκ and TP53 status on melanomagenesis.

Main Results:

  • RAS at the Golgi complex is selectively activated by apoptogenic stimuli.
  • Golgi-localized RAS suppresses ERK activity by inducing PTPRκ, which dephosphorylates CRAF, thereby antagonizing cell survival.
  • RAS at the Golgi complex does not induce melanoma in zebrafish, unlike plasma-membrane RAS.
  • Inactivation of PTPRκ, common in human melanoma and often coinciding with TP53 inactivation, accelerates RAS-ERK pathway-driven melanomagenesis in zebrafish.
  • TP53 disruption in zebrafish facilitates oncogenesis driven by Golgi-localized RAS.

Conclusions:

  • RAS oncogenic potential is strictly dependent on its sublocalization within the cell.
  • Golgi complex-localized RAS acts as a tumor suppressor by antagonizing cell survival pathways.
  • The interplay between RAS localization, PTPRκ, and TP53 status is critical in regulating melanomagenesis.

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