Browsing by Subject "Dipeptidyl peptidase 4"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    DPP4+ exosomes in AML patients’ plasma suppress proliferation of hematopoietic progenitor cells
    (Springer Nature, 2021) Namburi, Swathi; Broxmeyer, Hal E.; Hong, Chang-Sook; Whiteside, Theresa L.; Boyiadzis, Michael; Microbiology and Immunology, School of Medicine
    Mechanisms by which acute myeloid leukemia (AML) interferes with normal hematopoiesis are under intense investigation. Emerging evidence suggests that exosomes produced by leukemia blasts suppress hematopoiesis. Exosomes isolated from AML patients' plasma at diagnosis significantly and dose-dependently suppressed colony formation of normal hematopoietic progenitor cells (HPC). Levels of HPC suppression mediated by exosomes of AML patients who achieved complete remission (CR) were significantly decreased compared to those observed at AML diagnosis. Exosomes from plasma of patients who had achieved CR but with incomplete cell count recovery (CRi) after chemotherapy suppressed in vitro colony formation as effectively as did exosomes obtained at AML diagnosis. Dipeptidylpeptidase4 (DPP4/CD26), a serine protease that cleaves select penultimate amino acids of various proteins, has been previously implicated in the regulation of hematopoiesis. DPP4 was carried by exosomes from AML plasma or leukemia cell lines. Leukemia exosomes which suppressed HSC colony formation had markedly higher DPP4 functional activity than that detected in the exosomes of normal donors. Pharmacological inhibition of DPP4 activity in AML exosomes reversed the effects of exosome-mediated myelosuppression. Reversing the negative effects of exosomes on AML hematopoiesis, and thus improving cell count recovery, might emerge as a new therapeutic approach to AML.
  • Thumbnail Image
    Item
    An expanded role for Dipeptidyl peptidase 4 (DPP4) in cell regulation
    (Wolters Kluwer, 2020) Ropa, James; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Purpose of review: Dipeptidyl peptidase 4 (DPP4) is a serine protease with diverse regulatory functions in healthy and diseased cells. Much remains unknown about the mechanisms and targets of DPP4. Here we discuss new studies exploring DPP4-mediated cellular regulation, provide an updated list of potential targets of DPP4, and discuss clinical implications of each. Recent findings: Recent studies have sought enhanced efficacy of targeting DPP4's role in regulating hematopoietic stem and progenitor cells for improved clinical application. Further studies have identified DPP4 functions in different cellular compartments and have proposed ways to target this protein in malignancy. These findings, together with an expanded list of putative extracellular, cell surface, and intracellular DPP4 targets, provide insight into new DPP4-mediated cell regulation. Summary: DPP4 posttranslationally modifies proteins and peptides with essential roles in hematopoietic cell regulation, stem cell transplantation, and malignancy. Targets include secreted signaling factors and may include membrane proteins and transcription factors critical for different hematopoietic functions. Knowing these targets and functions can provide insight into new regulatory roles for DPP4 that may be targeted to enhance transplantation, treat disease, and better understand different regulatory pathways of hematopoiesis.
  • Thumbnail Image
    Item
    What doesn't kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands
    (Elsevier, 2019) Elmansi, Ahmed M.; Awad, Mohamed E.; Eisa, Nada H.; Kondrikov, Dmitry; Hussein, Khaled A.; Aguilar-Pérez, Alexandra; Herberg, Samuel; Periyasamy-Thandavan, Sudharsan; Fulzele, Sadanand; Hamrick, Mark W.; McGee-Lawrence, Meghan E.; Isales, Carlos M.; Volkman, Brian F.; Hill, William D.; Anatomy and Cell Biology, IU School of Medicine
    Dipeptidyl peptidase 4 (DPP4) is an exopeptidase found either on cell surfaces where it is highly regulated in terms of its expression and surface availability (CD26) or in a free/circulating soluble constitutively available and intrinsically active form. It is responsible for proteolytic cleavage of many peptide substrates. In this review we discuss the idea that DPP4-cleaved peptides are not necessarily inactivated, but rather can possess either a modified receptor selectivity, modified bioactivity, new antagonistic activity, or even a novel activity relative to the intact parent ligand. We examine in detail five different major DPP4 substrates: glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide tyrosine-tyrosine (PYY), and neuropeptide Y (NPY), and stromal derived factor 1 (SDF-1 aka CXCL12). We note that discussion of the cleaved forms of these five peptides are underrepresented in the research literature, and are both poorly investigated and poorly understood, representing a serious research literature gap. We believe they are understudied and misinterpreted as inactive due to several factors. This includes lack of accurate and specific quantification methods, sample collection techniques that are inherently inaccurate and inappropriate, and a general perception that DPP4 cleavage inactivates its ligand substrates. Increasing evidence points towards many DPP4-cleaved ligands having their own bioactivity. For example, GLP-1 can work through a different receptor than GLP-1R, DPP4-cleaved GIP can function as a GIP receptor antagonist at high doses, and DPP4-cleaved PYY, NPY, and CXCL12 can have different receptor selectivity, or can bind novel, previously unrecognized receptors to their intact ligands, resulting in altered signaling and functionality. We believe that more rigorous research in this area could lead to a better understanding of DPP4’s role and the biological importance of the generation of novel cryptic ligands. This will also significantly impact our understanding of the clinical effects and side effects of DPP4-inhibitors as a class of anti-diabetic drugs that potentially have an expanding clinical relevance. This will be specifically relevant in targeting DPP4 substrate ligands involved in a variety of other major clinical acute and chronic injury/disease areas including inflammation, immunology, cardiology, stroke, musculoskeletal disease and injury, as well as cancer biology and tissue maintenance in aging.