Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA

Tobias Schmid; L Basten Snoek; Erika Fröhli; M Leontien van der Bent; Jan Kammenga; Alex Hajnal

doi:10.1371/journal.pgen.1005236

Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA

PLoS Genet. 2015 May 15;11(5):e1005236. doi: 10.1371/journal.pgen.1005236. eCollection 2015 May.

Authors

Tobias Schmid¹, L Basten Snoek², Erika Fröhli³, M Leontien van der Bent², Jan Kammenga², Alex Hajnal³

Affiliations

¹ University of Zurich, Institute of Molecular Life Sciences, Zurich, Switzerland; PhD Program in Molecular Life Sciences, University and ETH Zurich, Zurich, Switzerland.
² Laboratory of Nematology, Wageningen University, Wageningen, The Netherlands.
³ University of Zurich, Institute of Molecular Life Sciences, Zurich, Switzerland.

Abstract

Human cancer is caused by the interplay of mutations in oncogenes and tumor suppressor genes and inherited variations in cancer susceptibility genes. While many of the tumor initiating mutations are well characterized, the effect of genetic background variation on disease onset and progression is less understood. We have used C. elegans genetics to identify genetic modifiers of the oncogenic RAS/MAPK signaling pathway. Quantitative trait locus analysis of two highly diverged C. elegans isolates combined with allele swapping experiments identified the polymorphic monoamine oxidase A (MAOA) gene amx-2 as a negative regulator of RAS/MAPK signaling. We further show that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is a product of MAOA catalysis, systemically inhibits RAS/MAPK signaling in different organs of C. elegans. Thus, MAOA activity sets a global threshold for MAPK activation by controlling 5-HIAA levels. To our knowledge, 5-HIAA is the first endogenous small molecule that acts as a systemic inhibitor of RAS/MAPK signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Caenorhabditis elegans / genetics
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / metabolism
Chromosome Mapping
Gene Expression Regulation*
Genotyping Techniques
Hydroxyindoleacetic Acid / chemistry*
MAP Kinase Signaling System*
Monoamine Oxidase / genetics
Monoamine Oxidase / metabolism
Protein Kinase Inhibitors / chemistry*
Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
Quantitative Trait Loci
Serotonin / chemistry*
Signal Transduction

Substances

Caenorhabditis elegans Proteins
Protein Kinase Inhibitors
Serotonin
Hydroxyindoleacetic Acid
Monoamine Oxidase
Proto-Oncogene Proteins p21(ras)

Grants and funding

This work was supported by the Kanton of Zurich, the PANACEA EU FP project contract nr. 222936 and a grant from the Swiss National Science Foundation to AH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.