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. DOI: http://dx.doi.org/10.7554/eLife.16370.001

• Publication year

  2016

• Venue

  eLife

• Publication date

  2016-09-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.7554/eLife.16370PMID 27614019PMCID 5039030
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• PROTEOLYTC FUNCTION OF N-TERMINAL ACETYLATION OF CELLULAR PROTEINS

  2017influential reference
• Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

  2016cited by this paper
• Dipeptidyl peptidase 9 enzymatic activity influences the expression of neonatal metabolic genes.

  2016cited by this paper
• Degradation of the Separase-cleaved Rec8, a Meiotic Cohesin Subunit, by the N-end Rule Pathway*

  2016cited by this paper
• The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis

  2015cited by this paper
• Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer.

  2015cited by this paper
• Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway

  2015cited by this paper
• Dipeptidyl peptidase 9 subcellular localization and a role in cell adhesion involving focal adhesion kinase and paxillin.

  2015influential reference
• Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation

  2015cited by this paper
• Inhibition of dipeptidyl peptidase 8/9 impairs preadipocyte differentiation

  2015cited by this paper
• Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

  2014cited by this paper
• The Role of the Syk/Shp-1 Kinase-Phosphatase Equilibrium in B Cell Development and Signaling

  2014cited by this paper
• Dipeptidyl peptidases in atherosclerosis: expression and role in macrophage differentiation, activation and apoptosis

  2013cited by this paper
• Inhibition of intracellular dipeptidyl peptidases 8 and 9 enhances parthenolide’s anti-leukemic activity

  2013cited by this paper
• Neurodegeneration-associated protein fragments as short-lived substrates of the N-end rule pathway.

  2013cited by this paper
• The SUMO1-E67 Interacting Loop Peptide Is an Allosteric Inhibitor of the Dipeptidyl Peptidases 8 and 9*

  2013influential reference
• Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway.

  2013cited by this paper
• Targeted Inactivation of Dipeptidyl Peptidase 9 Enzymatic Activity Causes Mouse Neonate Lethality

  2013influential reference
• Complex roles of filamin-A mediated cytoskeleton network in cancer progression

  2013influential reference
• Advances in Understanding the Expression and Function of Dipeptidyl Peptidase 8 and 9

  2013cited by this paper
• Structural and biophysical characterization of the Syk activation switch.

  2012cited by this paper
• The N-end rule pathway.

  2012cited by this paper
• A Novel SUMO1-specific Interacting Motif in Dipeptidyl Peptidase 9 (DPP9) That Is Important for Enzymatic Regulation*

  2012cited by this paper
• The N‐end rule pathway and regulation by proteolysis

  2011cited by this paper
• Structure-activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9): is DPP8-selectivity an attainable goal?

  2011cited by this paper
• A Novel Role of Dipeptidyl Peptidase 9 in Epidermal Growth Factor Signaling

  2011influential reference
• Complex phosphorylation dynamics control the composition of the Syk interactome in B cells

  2011cited by this paper
• Src-family and Syk kinases in activating and inhibitory pathways in innate immune cells: signaling cross talk.

  2011cited by this paper
• The filamins

  2011cited by this paper
• The N-end rule pathway is mediated by a complex of the RING-type Ubr1 and HECT-type Ufd4 ubiquitin ligases

  2010cited by this paper
• Protein N-terminal processing: substrate specificity of Escherichia coli and human methionine aminopeptidases.

  2010cited by this paper
• N-Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals

  2010influential reference
• The SYK tyrosine kinase: a crucial player in diverse biological functions

  2010cited by this paper
• The dipeptidyl peptidase IV family in cancer and cell biology

  2010cited by this paper
• Filamins in cell signaling, transcription and organ development.

  2010cited by this paper
• A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

  2010cited by this paper
• Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans

  2009cited by this paper
• The Cytoplasmic Peptidase DPP9 Is Rate-limiting for Degradation of Proline-containing Peptides*

  2009influential reference
• Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor.

  2009cited by this paper
• Syk and pTyr'd: Signaling through the B cell antigen receptor.

  2009cited by this paper
• The Substrate Recognition Domains of the N-end Rule Pathway*

  2009cited by this paper
• Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety.

  2008cited by this paper
• Molecular Mechanism of the Syk Activation Switch*

  2008cited by this paper
• Structural basis of filamin A functions

  2007cited by this paper
• Syk‐dependent ERK activation regulates IL‐2 and IL‐10 production by DC stimulated with zymosan

  2007cited by this paper
• Subcellular localization of Grb2 by the adaptor protein Dok‐3 restricts the intensity of Ca2+ signaling in B cells

  2007cited by this paper
• Ca2+ signaling in antigen receptor‐activated B lymphocytes

  2007cited by this paper
• Protein tyrosine phosphatase receptor-type O truncated (PTPROt) regulates SYK phosphorylation, proximal B-cell-receptor signaling, and cellular proliferation.

  2006cited by this paper
• The Proteomics of N-terminal Methionine Cleavage*S

  2006cited by this paper
• The Syk tyrosine kinase: a new negative regulator in tumor growth and progression.

  2006cited by this paper
• ITAM-mediated tonic signalling through pre-BCR and BCR complexes

  2006cited by this paper
• Structural basis for the functional differences between type I and type II human methionine aminopeptidases.

  2005cited by this paper
• A Family of Mammalian E3 Ubiquitin Ligases That Contain the UBR Box Motif and Recognize N-Degrons

  2005cited by this paper
• Dipeptidyl peptidase 9 has two forms, a broad tissue distribution, cytoplasmic localization and DPIV-like peptidase activity.

  2004cited by this paper
• Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases.

  2003cited by this paper
• Cbl-b Negatively Regulates B Cell Antigen Receptor Signaling in Mature B Cells through Ubiquitination of the Tyrosine Kinase Syk

  2003influential reference
• The non‐receptor tyrosine kinase Syk is a target of Cbl‐mediated ubiquitylation upon B‐cell receptor stimulation

  2001cited by this paper
• Degradation of a cohesin subunit by the N-end rule pathway is essential for chromosome stability

  2001cited by this paper
• Ubiquitination and degradation of Syk and ZAP-70 protein tyrosine kinases in human NK cells upon CD16 engagement

  2001influential reference
• The RING Finger Domain of Cbl Is Essential for Negative Regulation of the Syk Tyrosine Kinase*

  2000influential reference
• The F-box protein family

  2000cited by this paper
• Expression of dominant-negative src-homology domain 2-containing protein tyrosine phosphatase-1 results in increased Syk tyrosine kinase activity and B cell activation.

  1999cited by this paper
• Inhibition of signaling through the B cell antigen receptor by the protooncogene product, c-Cbl, requires Syk tyrosine 317 and the c-Cbl phosphotyrosine-binding domain.

  1999influential reference
• The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase.

  1999cited by this paper
• Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide.

  1998cited by this paper
• Cbl-mediated Negative Regulation of the Syk Tyrosine Kinase

  1998influential reference
• The product of the proto-oncogene c-cbl: a negative regulator of the Syk tyrosine kinase.

  1997cited by this paper
• A truncated heavy chain protein relieves the requirement for surrogate light chains in early B cell development.

  1997cited by this paper
• Phospholipase C-gamma1 interacts with conserved phosphotyrosyl residues in the linker region of Syk and is a substrate for Syk

  1996cited by this paper
• Phospholipase C- (cid:103) 1 Interacts with Conserved Phosphotyrosyl Residues in the Linker Region of Syk and Is a Substrate for Syk

  1996cited by this paper
• Evidence for a preformed transducer complex organized by the B cell antigen receptor.

  1996cited by this paper
• Cloning, expression and identification of the major sites of autophosphorylation of the murine protein-tyrosine kinase Syk

  1996cited by this paper
• The degradation signal in a short-lived protein.

  1989cited by this paper
• [What a family!].

  1989cited by this paper
• Cellular and Molecular Life Sciences the Amino Terminus Extension in the Long Dipeptidyl Peptidase 9 Isoform Contains a Nuclear Localization Signal Targeting the Active Peptidase to the Nucleus

  year unknowncited by this paper

• Proximity labeling reveals non-catalytic interactions between DPP9 and ubiquitin signaling complexes

  2026cites this paper
• Dipeptidyl Peptidase 9 in Human Leukocytes: Novel Inhibitors Induce Caspase‐1‐ and Gasdermin‐Dependent Cell Death

  2025cites this paper
• A fluorescent sensor for real-time monitoring of DPP8/9 reveals crucial roles in immunity and cancer

  2025cites this paper
• A Photocaged N‐Phosphonopiperidinone as a Selective Photo‐Cleavable DPP8/9 Inhibitor

  2025cites this paper
• Small-molecule degron mimetics for targeted protein degradation

  2025cites this paper
• NLRP1 under pressure: An overview of the NLRP1 inflammasome as a sensor of cellular stress.

  2025cites this paper
• The multifunctional regulatory post-proline protease dipeptidyl peptidase 9 and its inhibitors: new opportunities for therapeutics

  2025influential citation
• DPP9 regulates NQO1 and ROS to promote resistance to chemotherapy in liver cancer cells

  2024cites this paper
• Dipeptidyl peptidases and E3 ligases of N-degron pathways cooperate to regulate protein stability

  2024cites this paper
• Dipeptidyl-peptidase 9 regulates the dynamics of tumorigenesis and metastasis in breast cancer.

  2024cites this paper
• N-terminal processing by dipeptidyl peptidase 9: Cut and Go!

  2024cites this paper
• Hippocampal Dipeptidyl Peptidase 9 Bidirectionally Regulates Memory Via Synaptic Plasticity

  2024cites this paper
• The serine protease DPP9 and the redox sensor KEAP1 form a mutually inhibitory complex

  2024cites this paper
• In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms.

  2024cites this paper
• An Interdisciplinary Approach Provides Insights into the Pronounced Selectivity of Compound 42 for DPP9

  2024cites this paper
• Hippocampal dipeptidyl peptidase 9 bidirectionally regulates memory associated with synaptic plasticity

  2024cites this paper
• N-degron pathways

  2024cites this paper
• DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies

  2023cites this paper
• Development of the dipeptidyl peptidase 4 family and its association with lung diseases: a narrative review

  2023cites this paper
• Dipeptidyl-Aminopeptidases 8 and 9 Regulate Autophagy and Tamoxifen Response in Breast Cancer Cells

  2023cites this paper
• The amino-dipeptidyl peptidases DPP8 and DPP9: Purification and enzymatic assays.

  2023cites this paper
• DPP8/9 are not Required to Cleave Most Proline-Containing Peptides.

  2023cites this paper
• Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair

  2022influential citation
• Crystal structure of the Ate1 arginyl-tRNA-protein transferase and arginylation of N-degron substrates

  2022cites this paper
• Chemoproteomics‐Enabled Identification of 4‐Oxo‐β‐Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9

  2022cites this paper
• New insights into the role of dipeptidyl peptidase 8 and dipeptidyl peptidase 9 and their inhibitors

  2022cites this paper
• DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling

  2022cites this paper
• Associations between DPP9 expression, survival and gene expression signature in human hepatocellular carcinoma: Comprehensive in silico analyses

  2021cites this paper
• DPP9: Comprehensive In Silico Analyses of Loss of Function Gene Variants and Associated Gene Expression Signatures in Human Hepatocellular Carcinoma

  2021cites this paper
• BAFF Promotes Heightened BCR Responsiveness and Manifestations of Chronic GVHD after Allogeneic Stem Cell Transplantation.

  2021cites this paper
• DPP9 deficiency: an inflammasomopathy which can be rescued by lowering NLRP1/IL-1 signaling

  2021cites this paper
• The Arg/N-Degron Pathway—A Potential Running Back in Fine-Tuning the Inflammatory Response?

  2020cites this paper
• Recognition of nonproline N-terminal residues by the Pro/N-degron pathway

  2020cites this paper
• Protease-mediated processing of Argonaute proteins controls small RNA association

  2020cites this paper
• Human proline specific peptidases: A comprehensive analysis.

  2020cites this paper
• Dipeptidyl peptidase 9 triggers BRCA2 degradation by the N-degron pathway to promote DNA-damage repair

  2020cites this paper
• Gid10 as an alternative N-recognin of the Pro/N-degron pathway

  2019cites this paper
• CD26/DPP4 - a potential biomarker and target for cancer therapy.

  2019influential citation
• N-degron and C-degron pathways of protein degradation

  2019cites this paper
• Tetrandrine enhances the ubiquitination and degradation of Syk through an AhR-c-src-c-Cbl pathway and consequently inhibits osteoclastogenesis and bone destruction in arthritis

  2019cites this paper
• When Degradation Elicits the Alarm: N-Terminal Degradation of NLRP1B Unleashes Its Inflammasome Activity.

  2019cites this paper
• Improvement of Protein Crystal Diffraction Using Post- Crystallization Methods: Infrared Laser Radiation Controls Crystal Order

  2019cites this paper
• A Chemical Strategy for Protease Substrate Profiling.

  2019cites this paper
• Critical Structural Defects Explain Filamin A Mutations Causing Mitral Valve Dysplasia.

  2019cites this paper
• Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer

  2018cites this paper
• Tetrandrine attenuates the bone erosion in collagen‐induced arthritis rats by inhibiting osteoclastogenesis via spleen tyrosine kinase

  2018cites this paper
• Emerging branches of the N-end rule pathways are revealing the sequence complexities of N-termini dependent protein degradation.

  2018influential citation
• Immune regeneration in irradiated mice is not impaired by the absence of DPP9 enzymatic activity

  2018cites this paper
• DPP9 is an endogenous and direct inhibitor of the NLRP1 inflammasome that guards against human auto-inflammatory diseases

  2018cites this paper
• Human Platelet Protein Ubiquitylation and Changes following GPVI Activation

  2018cites this paper
• Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding

  2018cites this paper
• The expression of proline-specific enzymes in the human lung.

  2017cites this paper
• Investigating the biological importance of Dipeptidyl Peptidase 9 enzymatic activity using a mouse model

  2016cites this paper