Physiologic and pathologic SMYD3 lysine methylation signaling – S3S

Post-translational protein modifications (PTMs) contribute to all aspects of cell physiology and are a primary source of protein functional diversity in mammalian cells. Such modifications add another layer of coded information that can finely tune the transmission of intracellular signaling. A highly regulated set of enzymes catalyzes the addition and removal of PTMs. For example, the chemical addition of methyl moieties to lysine residues is catalyzed by lysine methyltransferases (KMTs).
Lysine methylation of histone proteins are known to fundamentally regulate chromatin function, however there is a growing appreciation that a number of non-histone proteins undergo lysine methylation too. Thus, it is likely that many proteins involved in cell homeostasis are methylated and that deregulation in protein methylation signaling may play a role in various diseases. Indeed, there is an increasing evidence of aberrant regulation of KTMs in human pathologies. Despite the fundamental role for this modification in biology, the catalytic activity and substrate specificity for the majority of KMT enzymes has been little studied and relatively few protein lysine methylation substrates have been identified and functionally characterized.
The KMT SMYD3 (SET and MYND domain containing protein 3) is highly overexpressed in several cancers and studies suggest that its overexpression promotes cell proliferation, while its depletion decreases tumor progression. However, its physiologic functions remain unclear with evidences suggesting a function in stem cell differentiation as well as in skeletal and cardiac muscles formation. Its activity has been linked to the regulation of gene expression programs in the nucleus, including proliferation programs and estrogen receptor (ER) controlled genes, suggesting that SMYD3 may directly regulate transcription via histone methylation. However, SMYD3 is preferentially cytoplasmic in various cell lines.
KMTs are almost certain to have different substrates and to affect various cell signals. Thus, knowledge of SMYD3 cytoplasmic and nuclear substrates will be essential to understand how its activity influences biological processes. For example, I discovered during my previous postdoc in Or Gozani laboratory at Stanford University a new methylated substrate for SMYD3, MAP3K2, and demonstrated how this methylation participates in the deregulation of the ERK1/2 signaling in Ras-dependent lung cancer.
Our proposal aims to investigate the mechanism of action of SMYD3 methyltransferase in mammalian cells and to identify novel substrates and signaling pathways to understand its physiologic and pathologic functions. Our work will focus on two specific contexts with evidences of SMYD3’s implication: muscle formation and regeneration, and pancreatitis.
Using proteomics and molecular biology tools, we will identify novel lysine methylation events catalyzed by SMYD3. The characterization of these novel signalings will furthermore be assessed with genetic and pharmacologic inhibition of SMYD3 and its substrates in cell lines and mouse models, in order to understand consequences of each methylation events on their targeted proteins’ activity depending of their specific biological context.
As a young scientist, I expect to develop a successful research on SMYD3 lysine methylation signaling, and the ANR JCJC 2016 will help me to identify myself as a young group leader. I am already mentoring a PhD student and a technician on this project and I have the complete support of Albert Bonniot Institute’s director Pierre Hainaut for the development of my proposal.