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Golgi RAS suppresses cancer by blocking MAPK

Golgi RAS suppresses cancer by blocking MAPK

Unearthing a tumor suppressor function for RAS, which down-regulates MAPK signalling.

Golgi RAS suppresses cancer by blocking MAPK

Full title

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

 

Journal

Nature Communications

 

Authors

Casar B, Badrock A, Jiménez I, Arozarena I, Colón-Bolea P, Lorenzo-Martín F, Barinaga-Rementeria Ramirez I, Barriuso J, Cappitelli V, Donoghue D, Bustelo X, Hurlstone A, and Crespo P

 

Unearthing a tumor suppressor function for RAS, which down-regulates MAPK signalling.

The authors unearthed a tumor suppressor function for RAS, known only as an oncogene, localized at the Golgi complex through induction of a tyrosine phosphatase, PTPRk, which down-regulates MAPK signalling.

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.

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.

Key facts

  • RAS, known only as an oncogene, located at the Golgi is a tumor suppressor.
  • Golgi RAS induces the phosphatase PTPRk.
  • PTPRk antagonises MAPK signalling.
  • PTPRk is mutated and down-regulated in melanoma.
  • Loss of PTPRk promotes melanoma formation.

Contributing authors

Partners

Footnotes

Work in the Hurlstone laboratory was funded by a grant from the European Research Council (ERC-2011-StG-282059 PROMINENT).