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

Ahmed M. Elmansi, Mohamed E. Awad, Nada H. Eisa, Dmitry Kondrikov, Khaled A. Hussein, Alexandra Aguilar-Pérez, Samuel Herberg, Sudharsan Periyasamy-Thandavan, Sadanand T Fulzele, Mark W Hamrick, Meghan Elizabeth McGee Lawrence, Carlos M Isales, Brian F. Volkman, William D. Hill

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)90-108
Number of pages19
JournalPharmacology and Therapeutics
Volume198
DOIs
StatePublished - Jun 1 2019

Fingerprint

Dipeptidyl Peptidase 4
Peptide Hormones
Proteolysis
Cytokines
Ligands
Peptides
Glucagon-Like Peptide 1
Neuropeptide Y
tyrosyltyrosine
Exopeptidases
Research
Gastric Inhibitory Polypeptide
Musculoskeletal Diseases
Dipeptidyl-Peptidase IV Inhibitors
Wounds and Injuries
Allergy and Immunology
Cardiology
Chronic Disease
Stroke
Maintenance

Keywords

  • CXCL12
  • Dipeptidyl peptidase 4
  • glucagon-like peptide 1
  • glucose-dependent insulinotropic polypeptide
  • neuropeptide Y
  • peptide tyrosine-tyrosine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

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. / Elmansi, Ahmed M.; Awad, Mohamed E.; Eisa, Nada H.; Kondrikov, Dmitry; Hussein, Khaled A.; Aguilar-Pérez, Alexandra; Herberg, Samuel; Periyasamy-Thandavan, Sudharsan; Fulzele, Sadanand T; Hamrick, Mark W; McGee Lawrence, Meghan Elizabeth; Isales, Carlos M; Volkman, Brian F.; Hill, William D.

In: Pharmacology and Therapeutics, Vol. 198, 01.06.2019, p. 90-108.

Research output: Contribution to journalArticle

Elmansi, Ahmed M. ; Awad, Mohamed E. ; Eisa, Nada H. ; Kondrikov, Dmitry ; Hussein, Khaled A. ; Aguilar-Pérez, Alexandra ; Herberg, Samuel ; Periyasamy-Thandavan, Sudharsan ; Fulzele, Sadanand T ; Hamrick, Mark W ; McGee Lawrence, Meghan Elizabeth ; Isales, Carlos M ; Volkman, Brian F. ; Hill, William D. / 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. In: Pharmacology and Therapeutics. 2019 ; Vol. 198. pp. 90-108.
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AU - Awad, Mohamed E.

AU - Eisa, Nada H.

AU - Kondrikov, Dmitry

AU - Hussein, Khaled A.

AU - Aguilar-Pérez, Alexandra

AU - Herberg, Samuel

AU - Periyasamy-Thandavan, Sudharsan

AU - Fulzele, Sadanand T

AU - Hamrick, Mark W

AU - McGee Lawrence, Meghan Elizabeth

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AU - Volkman, Brian F.

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