DPP9 is a novel component of the N-end rule pathway targeting the Tyrosine Kinase Syk
- University Medical Center Goettingen, Germany
- MRC Laboratory of Molecular Biology, United Kingdom
- Harvard Medical School, United States
Abstract
The aminopeptidase DPP9 removes dipeptides from N-termini of substrates having a proline or alanine in second position. Although linked to several pathways including cell survival and metabolism, the molecular mechanisms underlying these outcomes are poorly understood. We identified a novel interaction of DPP9 with Filamin A, which recruits DPP9 to Syk, a central kinase in B-cell signalling. Syk signalling can be terminated by degradation, requiring the ubiquitin E3 ligase Cbl. We show that DPP9 cleaves Syk to produce a neo N-terminus with serine in position 1. Pulse-chases combined with mutagenesis studies reveal that Ser1 strongly influences Syk stability. Furthermore, DPP9 silencing reduces Cbl interaction with Syk, suggesting that DPP9 processing is a prerequisite for Syk ubiquitination. Consistently, DPP9 inhibition stabilizes Syk, thereby modulating Syk signalling. Taken together, we demonstrate DPP9 as a negative regulator of Syk and conclude that DPP9 is a novel integral aminopeptidase of the N-end rule pathway.
Article and author information
Author details
Ruth Geiss-Friedlander
Funding
Deutsche Forschungsgemeinschaft (2234/1-2)
- Ruth Geiss-Friedlander
Heidenreich von Siebold-Programm, Universitaetsmedizin Goettingen
- Ruth Geiss-Friedlander
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Justa-Schuch et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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DPP9 is a novel component of the N-end rule pathway targeting the Tyrosine Kinase Syk
eLife 5:e16370.
https://doi.org/10.7554/eLife.16370
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