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

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.