Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types

Abstract

Dipeptidylpeptidase (DPP) 4 has the potential to truncate proteins with a penultimate alanine, proline, or other selective amino acids at the N-terminus. DPP4 truncation of certain chemokines, colony-stimulating factors, and interleukins have recently been linked to regulation of hematopoietic stem/progenitor cells, more mature blood cells, and other cell types. We believe that the potential role of DPP4 in modification of many regulatory proteins, and their subsequent effects on numerous stem/progenitor and other cell-type functions has not been adequately appreciated. This review addresses the potential implications of the modifying effects of DPP4 on a large number of cytokines and other growth-regulating factors with either proven or putative DPP4 truncation sites on hematopoietic cells, and subsequent effects of DPP4-truncated proteins on multiple aspects of steady-state and stressed hematopoiesis, including stem/progenitor cell, and more mature cell, function.

Figure 1

Potential enhancement or inhibition resulting from DPP4 interactions with regulatory proteins. (A) Molecules that are stimulatory in the full-length form may lose activity after DPP4 truncation and act as competitive inhibitors by diminishing the function of the full-length protein through binding to the cognate receptor with higher affinity than that of the full-length molecule. (B) Molecules that are inhibitory in the full-length form may lose their suppressive ability when truncated by DPP4 and by binding to the cognate receptor with higher affinity, allowing for blockage of the full-length molecule’s suppressive activity. (C) Stimulatory or inhibitory molecules may increase their efficacy when truncated.

Figure 2

Additional possibilities for functional consequences of DPP4 truncation of regulatory proteins. (A) Truncated molecules do not bind to their receptor and may signal through other receptors. An example of this is full-length GLP-1, which binds to its cognate receptor but is truncated quickly and subsequently is unable to efficiently bind to the GLP-1 receptor and therefore does not inhibit, or alter the function, of the full-length molecule. Exenatide (Byetta) is a synthetic GLP-1 agonist made to mimic the GLP-1 homolog extendin-4, found in the saliva of the Gila monster. Exenatide is used in the treatment of type 2 diabetes because it is stable, binds to the GLP-1 receptor to induce insulin secretion, and is resistant to DPP4 truncation. (B) Factors without truncation sites may regulate factors with truncation sites by altering their expression, or function, and proteins with DPP4 truncation sites may regulate expression of proteins with or without DPP4 truncation sites.