Extraenzymatic functions of the dipeptidyl peptidase IV‐related proteins DP8 and DP9 in cell adhesion, migration and apoptosis

Abstract

The dipeptidyl peptidase IV gene family contains the four peptidases dipeptidyl peptidase IV, fibroblast activation protein, dipeptidyl peptidase 8 and dipeptidyl peptidase 9. Dipeptidyl peptidase IV and fibroblast activation protein are involved in cell–extracellular matrix interactions and tissue remodeling. Fibroblast activation protein is upregulated and dipeptidyl peptidase IV is dysregulated in chronic liver disease. The effects of dipeptidyl peptidase 8 and dipeptidyl peptidase 9 on cell adhesion, cell migration, wound healing and apoptosis were measured by using green fluorescent protein fusion proteins to identify transfected cells. Dipeptidyl peptidase 9‐overexpressing cells exhibited impaired cell adhesion, migration in transwells and monolayer wound healing on collagen I, fibronectin and Matrigel. Dipeptidyl peptidase 8‐overexpressing cells exhibited impaired cell migration on collagen I and impaired wound healing on collagen I and fibronectin in comparison to the green fluorescent protein‐transfected controls. Dipeptidyl peptidase 8 and dipeptidyl peptidase 9 enhanced induced apoptosis, and dipeptidyl peptidase 9 overexpression increased spontaneous apoptosis. Mechanistic investigations showed that neither the catalytic serine of dipeptidyl peptidase 8 or dipeptidyl peptidase 9 nor the Arg‐Gly‐Asp integrin‐binding motif in dipeptidyl peptidase 9 were required for the impairment of cell survival, cell adhesion or wound healing. We have previously shown that the in vitro roles of dipeptidyl peptidase IV and fibroblast activation protein in cell–extracellular matrix interactions and apoptosis are similarly independent of catalytic activity. Dipeptidyl peptidase 9 overexpression reduced β‐catenin, tissue inhibitor of matrix metalloproteinases 2 and discoidin domain receptor 1 expression. This is the first demonstration that dipeptidyl peptidase 8 and dipeptidyl peptidase 9 influence cell–extracellular matrix interactions, and thus may regulate tissue remodeling.

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

“…Both peptidases are ubiquitously expressed on mRNa levels in various organs and tissues and cell lines [18][19][20][21][22]. Changes in the levels of these peptidases appear to be critical for cell survival, as both overexpression or application of DPP8/9 inhibitors lead to cell death in several cell lines [23][24][25]. Recently, it was shown that knock-in mice with a serine to alanine mutation in the active site of DPP9 die 8-24 h after birth.…”

Contribution of upregulated dipeptidyl peptidase 9 (DPP9) in promoting tumoregenicity, metastasis and the prediction of poor prognosis in non‐small cell lung cancer (NSCLC)

“…Dipeptidyl peptidase 9 (DPP9) is a member of a family of ubiquitous atypical serine proteases,6 which mediate diverse physiological and pathological processes beyond incretin degradation, such as cell migration, tumor cell invasion, and metastasis 7, 8, 9. For example, the upregulation of DPP9 in human embryonic kidney (HEK293T) cells led to impaired cell adhesion and migration, as well as the enhancement of induced and spontaneous apoptosis 10. Emerging evidence has also revealed that disordered DPP9 expression may play a crucial role in cancer initiation and progression.…”

Expression of dipeptidyl peptidase-IV activity and/or structure homologs in human meningiomas

“…In contrast to the plasma membrane-bound DPP-IV/CD26 and FAP·, both these enzymes are cytosolic and therefore are not likely to process extracellular growth regulators. Besides their possible but unknown enzymatic intracellular functions, the enzyme activity-independent role of DPP8 and DPP9 in cell-ECM interactions has also been shown in cell culture (20).…”