Phosphoproteome dynamics reveal novel ERK1/2 MAP kinase substrates with broad spectrum of functions

Author:

Courcelles Mathieu12,Frémin Christophe1,Voisin Laure1,Lemieux Sébastien13,Meloche Sylvain14,Thibault Pierre125

Affiliation:

1. Institute for Research in Immunology and Cancer, Université de Montréal Montreal Quebec Canada

2. Department of Biochemistry, Université de Montréal Montreal Quebec Canada

3. Department of Informatics and Operational Research, Université de Montréal Montreal Quebec Canada

4. Department of Pharmacology, Université de Montréal Montreal Quebec Canada

5. Department of Chemistry, Université de Montréal Montreal Quebec Canada

Abstract

The ERK1/2 MAP kinase pathway is an evolutionarily conserved signaling module that controls many fundamental physiological processes. Deregulated activity of ERK1/2 MAP kinases is associated with developmental syndromes and several human diseases. Despite the importance of this pathway, a comprehensive picture of the natural substrate repertoire and biochemical mechanisms regulated by ERK1/2 is still lacking. In this study, we used large‐scale quantitative phosphoproteomics and bioinformatics analyses to identify novel candidate ERK1/2 substrates based on their phosphorylation signature and kinetic profiles in epithelial cells. We identified a total of 7936 phosphorylation sites within 1861 proteins, of which 155 classify as candidate ERK1/2 substrates, including 128 new targets. Candidate ERK1/2 substrates are involved in diverse cellular processes including transcriptional regulation, chromatin remodeling, RNA splicing, cytoskeleton dynamics, cellular junctions and cell signaling. Detailed characterization of one newly identified substrate, the transcriptional regulator JunB, revealed that ERK1/2 phosphorylate JunB on a serine adjacent to the DNA‐binding domain, resulting in increased DNA‐binding affinity and transcriptional activity. Our study expands the spectrum of cellular functions controlled by ERK1/2 kinases.

Publisher

Springer Science and Business Media LLC

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