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Pumping the brakes on RAS - negative regulators and death effectors of RAS

Desmond R Harrell Stewart1, Geoffrey J Clark2

  • 1Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY 40222, USA.

Journal of Cell Science
|February 12, 2020
PubMed

Insights

Aberrant RAS signaling drives cancer, often via defects in RAS regulators like Ras GTPase-activating proteins (RasGAPs). These proteins, including the RASSF family, suppress tumors through RAS-dependent and independent pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Activating mutations in RAS oncoproteins are frequent drivers of cancer.
  • RAS signaling can be aberrantly upregulated without RAS gene mutations, due to defects in RAS regulators.
  • Loss of function in Ras GTPase-activating proteins (RasGAPs) is common in tumors, with germline mutations causing clinical syndromes.

Purpose of the Study:

  • To examine the role of RAS effectors in tumor suppression.
  • To elucidate the mechanisms by which RasGAPs and the RASSF family contribute to tumor suppression.
  • To investigate both RAS-dependent and RAS-independent contributions to oncogenesis.

Main Methods:

  • Review of existing literature on RAS signaling pathways.
  • Analysis of the diverse binding partners and signaling mechanisms of RasGAPs.
  • Examination of the RASSF family's role in apoptosis, senescence, and RAS-mediated transformation.

Main Results:

  • RasGAPs regulate RAS activity but also impact signaling through RAS-independent mechanisms.
  • The RASSF family of tumor suppressors are critical for RAS-induced apoptosis and senescence.
  • Suppression of RASSF protein expression can lead to excessive RAS signaling by disrupting growth inhibitory pathways.

Conclusions:

  • RAS regulators, particularly RasGAPs and RASSF proteins, are crucial tumor suppressors.
  • These effectors contribute to tumor suppression via both direct RAS regulation and independent signaling pathways.
  • Understanding these mechanisms offers potential therapeutic targets for cancers with aberrant RAS activity.
Keywords:
DAB2IPGAPNF1RASRASA1RASAL2RASSF

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