Table 2.

Summary of molecules known to associate with dipeptidyl peptidase 4 (DPP4).

	Binding partner	Binding site	Function	Refs
Immunology	ADA	α1 and α2 of ADA bind to DPP4 via loop A between blades IV and V, and loop B between β 3 and β 4 of blade V, respectively. Glycosylation of DPP4‐Asn‐229 involved, as observed in crystal structure Ternary complex between A2BR‐ADA of dentritic APC to lymphocytic CD26. ADA binding only in higher mammalian and species‐dependent: human > porcine ≠ rat ≠ mouse	Binding of extracellular ADA to AB2 receptor on dentritic APC cells and CD26 on T cells to form a ternary complex, resulting in: co‐stimulation of T cells, T cell proliferation, T cell protection	7, 193 24
	CD45	Binding of DPP4 at the intracellular PTP2 domain of CD45 causes recruitment of both enzymes on lipid rafts	Signal transduction resulting in phosphorylation of Erk1/2TCR‐zeta, ZAP70 by p56lck	191
	M6P	Carbohydrate moiety of DPP4	Induces association of M6P/IGFRII and DPP4	190
	Caveolin‐1	Binding of caveolin‐1 on APC cells to soluble CD26 at aa 201–210 and Ser630 leading to: T cell proliferation + ⇑ CD26 on T cells ⇒ binding of CARMA‐1 on cytoplasmic tail of CD26 ⇒ phosphorylation of caveolin‐1 ⇒ dissociation of Tollip and IRAK‐1 ⇒ phosphorylation of IRAK‐1 ⇒ activation of NF‐κB ⇒ ⇑ CD86	Causes up‐regulation of CD86 on TT‐loaded dentritic monocytes, thus leading to the association of APC with CD28 on T cells and subsequently to T cell activation	189 114 112
	CARMA1(CARD11)	Binding of CARMA‐1 on cytoplasmic tail of CD26 ⇒ recruitment of CARMA‐1, CD26, Bcl10 and IkappaB kinase complex to lipid rafts ⇒ signal transduction	Leading to activation of ZAP70, PLC, MAPK, phosphatyl inositol and ⇑ IL‐2	112 112
	M6P/IGFRII	Needs M6P bound on DPP4	T cell activation, internalization of DPP4, transendothelial migration by binding of lymphocytes to endothelial DPP4	25 190
	CXCR4 receptor	?	Reduction of chemoattraction, co‐internalization in presence of SDF‐α, formation of invadopodia in presence of SDF‐α and gp120	194
	Tromoxane A2 receptor	?	Natural DPP4 inhibitor, T cell suppression	195
	HIV‐TAT	2 binding sites, sialic acid moiety and active site of DPP4 Crystal structures shows P2 and P1 of Tat1–9 bind to S1 and S2 of DPP4, respectively	HIV‐entry, inhibitor of DPP4 due to reverse binding at the active site	16, 24
	HIV‐gp120	Cysteine‐rich region, HIV‐gp 120 interacts via its C3 region with DPP4 on lymphocytes	HIV‐entry and subsequent apoptosis; inhibits ADA binding to DPP4 in presence of CXCR4, although binding site distinct to ADA	194
Cell adhesion/cell‐ cell communication	Collagen	Cysteine‐rich region between aa 238 and 495	Extracellular adhesion? Cancer? Metastasis?	196
	Fibronectin (FN)	Cysteine‐rich region of DPP4 between aa 469–479 via aa LTSRPA motif (FN)	Fibronectin‐mediated spreading of fibroblasts, lung metastasis, dissociates in presence of soluble DPP4	197
	Plasminogen receptor (PgR) Plasminogen/ Plasmin (Pg/Pl)	Cysteine‐rich region of DPP4 close to ADA binding site, sialic acid carbohydrate moieties of plasminogen binds to Pg‐receptor/DPP4 complex (aa 313–319)/αIIbβ3 and urinary/tissue plasminogen activator uPA/tPA. Activated plasmin (Pl) changes conformation and binds to DPP4. Quintary complex abolished by angiostatin binding to DPP4	⇑ Ca2+ response in synovial fibroblasts, activation of synovial fibroblasts, signal transduction in prostate cancer cells resulting in ⇑ MMP 9. Quintary complex of ADA, Pg 2, DPP4 and urinary plasminogen activator (uPA/tPA) and PgR ⇒ ⇑ Pg 2 to plasmin	198 199 5
	Streptokinase (SK)	Cysteine‐rich region of DPP4 only from rheumatoid synovial fibroblasts via aa LTSRPA motif (SK)	Ca2+ response in synovial fibroblasts, ⇑ DPP4 autoantibodies, SK bound to DPP4 hydrolysis FN	188 198
	Vitronectin	Sialic acid moiety of DPP4	Extracellular adhesion? Metastasis? Complement system? Coagulation?	16
	Glypican 3	Both glycosylated and unglycosylated glypican 3 bind to DPP4	Natural DPP4 inhibitor. Binding of soluble glypican 3 to CD26 ⇓ cell‐proliferation and induces apoptosis	200
	FAP	Heteromeric complex	Heteromeric complex on invadopodia causing metastasis, tumor invasion, angiogenesis, wound healing and fibroblast migration	201
	DPP4	Blades IV of each subunit align to form an eight‐stranded antiparallel sheet, possibly Asn229 involved	Tetramerization, cell‐adhesion, cell–cell communication?, chemotaxis?	202
Peptide transport	Na+/H+ exchanger isoform NH3	?	Peptide transporter on microvilli membrane of renal proximal tubule, reabsorption of dipeptides with proline. In prostate cancer, association of DPP4, Pg 2 and NH3 results in Ca2+ signal cascade and in intracellular pH ⇓ tumour cell‐proliferation + invasiveness	203 204