DPP9 is a novel component of the N-end rule pathway targeting the tyrosine kinase Syk

作者：Justa Schuch Daniela; Silva Garcia Maria; Pilla Esther; Engelke Michael; Kilisch Markus; Lenz Christof; Moeller Ulrike; Nakamura Fumihiko; Urlaub Henning; Geiss Friedlander Ruth

来源：eLife, 2016, 5: e16370.

DOI：10.7554/elife.16370

<jats:p>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.</jats:p>

• 出版日期2016-9-10