Enzymatic activity of DPIVCD26 is involved in PMA-induced hyperphosphorylation of p56lck

Kähne, Thilo; Neubert, Klaus; Ansorge, Siegfried

doi:10.1016/0165-2478(95)00041-3

Cited by 14 publications

(6 citation statements)

References 18 publications

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“…Indeed, it has been specifically demonstrated that DPPIV inhibitors affect tyrosine phosphorylation of multiple proteins in lymphocytes (23,24). Similarly, we found that the DPPIV inhibitor P32/98 decreased tyrosine phosphorylation of a high apparent molecular mass protein (Ͼ212 kDa) that coprecipitates with DPPIV, indicating a role for DPPIV in regulating tyrosine kinase signaling in OKP cells.…”

Section: Discussionmentioning

confidence: 48%

“…It is therefore of interest that DPPIV (CD26) regulation of cell proliferation and cytokine production in lymphocytes has been associated with changes in tyrosine kinase signaling (20,(22)(23)(24)36). Indeed, it has been specifically demonstrated that DPPIV inhibitors affect tyrosine phosphorylation of multiple proteins in lymphocytes (23,24).…”

Section: Discussionmentioning

confidence: 99%

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Role of dipeptidyl peptidase IV in regulating activity of Na⁺/H⁺ exchanger isoform NHE3 in proximal tubule cells

Girardi¹,

Knauf²,

Demuth³

et al. 2004

American Journal of Physiology-Cell Physiology

103

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We recently reported that NHE3 exists in multimeric complexes with dipeptidyl peptidase IV (DPPIV) in renal brush-border membranes. To examine the possible role of DPPIV in modulating NHE3 activity, we evaluated whether specific competitive inhibitors that bind to the active site of DPPIV affect NHE3 activity in the OKP line of opossum kidney proximal tubule cells. The DPPIV inhibitors diprotin A and P32/98 significantly reduced NHE3 activity, whereas the inactive isomer P34/98 had no effect. DPPIV inhibitors did not reduce the activity of another brush-border transport process, Na-phosphate cotransport. Effects of DPPIV inhibitors on NHE3 activity were not associated with detectable changes in amount or apparent molecular weight of NHE3 or in NHE3 surface expression. To investigate the signaling mechanisms involved in modulation of NHE3 activity by DPPIV, we used inhibitors of protein kinase pathways known to regulate NHE3. Whereas the PKA inhibitor H-89 failed to block the effect of DPPIV inhibitors, the tyrosine kinase inhibitor genistein alone caused a decrement in NHE3 activity very similar in magnitude to that caused by P32/98. We also found that the effects of genistein and P32/98 on NHE3 activity were not additive. In contrast, forskolin/ IBMX and P32/98 had additive inhibitory effects on NHE3 activity. These findings suggested that the effect of DPPIV inhibitors to reduce NHE3 activity results from inhibition of a tyrosine kinase signaling pathway rather than by activation of PKA. We conclude that DPPIV plays an unexpected role in modulating Na ϩ /H ϩ exchange mediated by NHE3 in proximal tubule cells. sodium/hydrogen exchange; diprotin A; P32/98; tyrosine kinase NA ϩ

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Role of dipeptidyl peptidase IV in regulating activity of Na⁺/H⁺ exchanger isoform NHE3 in proximal tubule cells

Girardi¹,

Knauf²,

Demuth³

et al. 2004

American Journal of Physiology-Cell Physiology

103

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“…DP IV/CD26 lacks an intracellular domain required for intracellular signalling. However, inhibition of DP IV activity suppresses early phosphorylation events in T‐cell activation in a dose‐dependent and reversible manner, as shown for hyperphosphorylation of p56lck [25]. In fact, it has been proposed that DP IV/CD26 associates with CD45 [20] which, in turn, regulates p56lck [26].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Dipeptidyl Peptidase IV (DP IV, CD26) Activity Abrogates Stress‐Induced, Cytokine‐Mediated Murine Abortions

et al. 2001

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In the CBA × DBA/2 mouse model, stress‐triggered abortions are mediated by a Th1‐like cytokine response of decidual lymphocytes. The factors that determine the cytokine pattern leading to abortion are currently unknown. Dipeptidyl Peptidase IV (DP IV) enhances Th1‐cytokine responses and impairs the evolvement of a Th2 cytokine profile. The T‐cell‐activation antigen, CD26, possesses DP IV activity. The aim of the present study was to investigate the role of DP IV activity and CD26‐positive decidual lymphocytes in murine stress‐triggered abortions by inhibition of DP IV activity. DBA/2‐mated CBA mice were stressed on day 5.5 of pregnancy and received daily injections of an inhibitor of DP IV activity, Ile‐thiazolidide (20 µmol/kg). On day 13 of gestation, the animals were sacrificed and the percentage of implants and abortions documented. CD26‐positive lymphocytes in spleen and uterine decidua and the intracellular cytokines interferon (IFN)‐γ and interleukin (IL)‐10 were determined by flow cytometry. Stressed and nonstressed animals receiving an inactive stereoisomeric form were used as controls. In mice receiving the DP IV inhibitor, stress failed to boost the abortion rate (37.2% versus 13.6%, P < 0.01). IFN‐γ producing cells were increased in stressed animals, but returned to the baseline upon the inhibition of DP IV. The number of IL‐10 producing cells was reduced in stressed animals, independent from DP IV inhibition.

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“…Some authors have described that small synthetic inhibitors of DPP IV impair lectin and antigen stimulation of peripheral blood mononuclear cells (PBMC) and other lymphocyte cell types [22]. A possible mechanism for this effect might be the inhibition of the hyperphosphorylation of the tyrosine kinase p56lck, a substrate of CD45, induced by DPP IV inhibitors [23], but the high concentrations of inhibitor required make such results questionable. The use of cell clones expressing a mutated, catalytically inactive, form of CD26 also gave contradictory results in two different cell lines, Jurkat [24] and BW2 [25].…”

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confidence: 99%

Dipeptidyl‐peptidase IV‐β

Blanco

Nguyen

Callebaut

et al. 1998

European Journal of Biochemistry

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Dipeptidyl peptidase IV-β (DPP IV-β) is a novel protein which shows a peptidase activity similar to the T-cell-activation antigen CD26. To further characterize this DPP IV-β and confirm its cell surface expression, we have developed a purification strategy using the CD26 Ϫ cell line C8166. The purification process includes biotinylation of cell surface proteins before preparation of cell extracts and processing by gel-filtration, ion-exchange and lectin chromatographies. Consistent with the molecular mass of DPP IV-β estimated by gel-filtration chromatography, the final purified fraction, manifesting a typical DPP IV activity, showed a major biotinylated 75Ϫ80-kDa band in SDS/PAGE, thus suggesting the monomeric nature of this enzyme. Kinetic parameters of DPP IV-β and the sensitivity to a new family of irreversible DPP IV inhibitors, were studied in comparison to CD26. Both enzymes followed a Michaelis kinetics with different K m values for Gly-Pro-NH-Np (NH-Np, para-nitroanilide) hydrolysis (0.28 Ϯ 0.05 mM and 0.12Ϯ0.02 mM). More significant differences were observed in the sensitivity to inhibitors, which exerted a much higher activity on CD26 than on DPP IV-β. These differences permitted us to study DPP IV-β expression in CD26-expressing cells, showing the expression of this new enzyme in all lymphoid cells tested, and a rapid enhancement in phytohemagglutinin-stimulated or protein-A-stimulated peripheral blood mononuclear cells. Our results indicate that, although DPP IV-β and CD26 are coexpressed and manifest a typical DPP IV activity, there are distinct features in their catalytic activities that may confer to each enzyme a complementary role in peptide processing.

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Enzymatic activity of DPIVCD26 is involved in PMA-induced hyperphosphorylation of p56lck

Cited by 14 publications

References 18 publications

Role of dipeptidyl peptidase IV in regulating activity of Na⁺/H⁺ exchanger isoform NHE3 in proximal tubule cells

Role of dipeptidyl peptidase IV in regulating activity of Na⁺/H⁺ exchanger isoform NHE3 in proximal tubule cells

Inhibition of Dipeptidyl Peptidase IV (DP IV, CD26) Activity Abrogates Stress‐Induced, Cytokine‐Mediated Murine Abortions

Dipeptidyl‐peptidase IV‐β

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Enzymatic activity of DPIVCD26 is involved in PMA-induced hyperphosphorylation of p56lck

Cited by 14 publications

References 18 publications

Role of dipeptidyl peptidase IV in regulating activity of Na+/H+ exchanger isoform NHE3 in proximal tubule cells

Role of dipeptidyl peptidase IV in regulating activity of Na+/H+ exchanger isoform NHE3 in proximal tubule cells

Inhibition of Dipeptidyl Peptidase IV (DP IV, CD26) Activity Abrogates Stress‐Induced, Cytokine‐Mediated Murine Abortions

Dipeptidyl‐peptidase IV‐β

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Role of dipeptidyl peptidase IV in regulating activity of Na⁺/H⁺ exchanger isoform NHE3 in proximal tubule cells

Role of dipeptidyl peptidase IV in regulating activity of Na⁺/H⁺ exchanger isoform NHE3 in proximal tubule cells