a potential global role for dipeptidylpeptidase 4 (dpp4/cd26) and its inhibition in the regulation...
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A Potential Global Role for Dipeptidylpeptidase 4 (DPP4/CD26) and Its Inhibition In The Regulation of
Hematopoiesis and Other Cell Systems
Hal E. Broxmeyer, PhD
Department of Microbiology/Immunology
Indiana University School of Medicine Indianapolis, Indiana, USA
Disclosure: Hal E. Broxmeyer, Ph.D.
Financial interests to disclose
Consulting:
Cord Use - a public cord blood banking company - MSAB and a founder of Cord Use Family Cord Blood Bank
Fate Therapeutics - Consultant
Since our initial scientific and clinical studies, Broxmeyer et al Proc. Natl. Acad. Science USA 86:3828-3832, 1989 Gluckman, Broxmeyer et al N. Engl. J. Med. 321: 1174-1178, 1989
there have now been over 30,000 cord blood transplants done to treat a wide variety of malignant and non-malignant disorders with hematopoietic stem cells
Broxmeyer, Farag, Rocha. 2013. Cord Blood Hematopoietic Cell Transplantation. In: Thomas’ Hematopoietic Cell Transplantation 5th Edition (Applebaum, Forman, Negrin, Antin, Eds) Wiley-Blackwell, England
Ballen, K.K., Gluckman, E., and Broxmeyer, H.E. 2013. Umbilical Cord Blood Transplantation – the first 25 years and beyond. Blood. In press
Goal
Understanding biology of HSC to enhance transplantation engraftment:
• CD26/Dipeptidylpeptidase (DPP) 4 influence on cytokine action, hematopoiesis, recovery from stress, and engrafting capability
A more global role for DPP4
CD26/DPPIV (dipeptidylpeptidase IV) cleaves dipeptides from the N-terminus
after a proline or an alanine
CD26/DPPIV
N- X1 - A/P2 - X3 - X4 … -C Cleavage of substrates after
the N-terminal pen-ultimate alanine or
proline
cleavage
Modulation of Hematopoietic Stem Cell Homing and Engraftment by CD26
K.W. Christophersen, Giao Hangoc, Charlie Mantel and Hal E. Broxmeyer
Science 30:1000-1003, 2004
CD26/Dipeptidylpeptidase IV Negatively Regulates Colony Stimulating Factor Activity and Stress Hematopoiesis
Hal E. Broxmeyer, Jonathan Hoggatt, Heather O’Leary, Charlie Mantel, Brahmananda R. Chitteti, Scott H. Cooper,
Steven Messina-Graham, Giao Hangoc, Sherif Farag, Sara L. Rohrabaugh, Xuan Ou, Jennifer Speth, Louis M. Pelus,
Edward F. Srour and Timothy B. Campbell
Nature Medicine 18: 1786-1796, 2012
In addition to SDF-1/CXCL12 and a number of other chemokines, there are other cytokines
that have putative CD26 truncation sites
Growth Factor Species Full length N-terminus Predicted
Mass Truncated N- Terminus Predicted Mass
GM-CSF Human APARSPSPSTQPWEH… 14,469 ARSPSPSTQPWEH… 14,301
Mouse APTRSPITVTRPWKH… 14,112 TRSPITVTRPWKH… 13,944
G-CSF Human TPLGPASSLPQSFLL… 18,661 LGPASSLPQSFLL… 18,463
Mouse VPLVTVSALPPSLPL… 18,940 LVTVSALPPSLPL… 18,744
IL-3 Human APMTQTTSLKTSWVN… 15,072 MTQTTSLKTSWVN… 14,904
Mouse ASISGRDTHRLTRTL… 15,673 N/A N/A
EPO Human APPRLICDSRVLERY… ~37 kDa † PRLICDSRVLERY… ~37 kDa †
Mouse APPRLICDSRVLERY… ~36 kDa † PRLICDSRVLERY… ~36 kDa †
M-CSF Human EEVSEYCSHMIGSGH… 18,403 * N/A N/A
Mouse KEVSEHCSHMIGNGH… 25,987 * N/A N/A
SCF Human EGICRNRVTNNVKDV… 18,458 N/A N/A
Mouse KEICGNPVTDNVKDI… 18,298 N/A N/A
FL Human TQDCSFQHSPISSDF… 18,050 N/A N/A
Mouse GTPDCYFSHSPISSN… 18,385 N/A N/A
* This may be in dimer form as well. † Glycosylated protein.
Cytokine
Cytokine + DPPIV(18 hrs)
Cytokine + Diprotin A + DPPIV (18 hrs)
GM-CSF IL-3
m/z14100 14600
Intensity
160
0
<14471>
m/z14100 14600Intensity
50
0
<14473>
m/z14100 14600
Intensity
18
0
14301
14470
m/z2000 20000
Intensity
160
0
14471
m/z2000 20000
Intensity
120
0
15080
m/z14700 15200Intensity
120
0
15080
m/z14700 15200
Intensity
40
0
14914
m/z14700 15200
Intensity
20
0
15085
Full Spectrum
14,471
14,471
14,301
14,473
15,080
15,080
15,085
14,914
Mass Spec Analysis of Human GM-CSF and IL-3
0 10 20 30 40 50 60 70 80 90 Colony Formation by Human Cord Blood Cells
Control DA w/ WASH
DA w/ NO WASH
Influence of Diprotin A Pretreatment of Human Cord Blood on Human Cytokine Stimulation of CFU-GM Colony Formation
rhuGM-CSF (20)
rhuGM-CSF (10)
rhuGM-CSF (1)
rhuG-CSFmet (20)
rhuG-CSFmet (10)
rhuG-CSFmet (1)
rhuIL-3 (20)
rhuIL-3 (10)
rhuIL-3 (1)
rhuM-CSF (1000)
rhuM-CSF (100)
rhuM-CSF (10)
rhuFlt3L
rhuSCF
rhuG-CSF (20)
rhuG-CSFmet (20)
Influence of Diprotin A (DPA) Pretreatment of Mouse Bone Marrow or Human Cord Blood on EPO Stimulation of BFU-E colony
Formation
Mouse Bone Marrow Stimulated by Recombinant Mouse (N=3) or Human (N=3) EPO
Human Cord Blood Stimulated by Recombinant Human (N=5) EPO
[Fold Increase of +DiProtinA / -DiprotinA]
a p<0.01 for +DPA compared to -DPA
0 0.5 1 1.5 2 2.5
a
a
• DPP4-truncated CSFs were much less active than full length CSFs
• Truncated CSFs blocked the activity of their own full length CSF form, acting as a dominant negative form of CSF
additional information (in vitro)
Effects of CD26 -/- on Cytokine
Actions In Vivo.
Control EPO: Full Length EPO: Truncated EPO: FL+T
+/+ CD26 -/- 0
2
4
6
8
10
12
14
16
(3.8X)
(1.4X) (1.3X)
(6.3X)
(1.6X) (1.8X)
* *
* *
*
* *
* P<0.01, N=4/group; 10U EPO (FL, T) or 10U each FL or T s.c. Blood assessed 24 hrs later
Influence of EPO On % PB Reticulocytes
Effects of Full Length and Truncated rmuGM-CSF, Alone and in Combination, on Absolute Numbers of Hematopoietic Progenitor Cells (HPC)
0 10 20 30 40 50 60 70 80
WT CD26
0 10 20 30 40 50 60 70 80
WT CD26
CFU-GM
HPC
per
Fem
ur (x
103 )
%
in S
-Pha
se
Control
GMCSF:Full Length (FL)
GMCSF:Truncated (T)
GMCSF:FL+T
Equilibrium receptor binding kinetic analysis using the factor dependent human
cell line, TF-1, as well as primary purified CD34+ cord blood cells demonstrated that:
• Truncated GM-CSF binds with higher affinity to GM-CSF receptor than does full length GM-CSF
• Truncated GM-CSF can block binding of full length GM-CSF
• This supports the functional progenitor cell GM-CSF stimulation assays that suggest that truncated GM-CSF can act as a negative regulator of full length GM-CSF function.
pJAK2
15 minutes
5 minutes
15 minute ratios
30 minutes
Unstimulated Full Length Truncated 1:1 5/10 2.5/10 1.25/10
N = 3 expts
% Ch
ange
in m
ean f
luores
cenc
e (m
ean +
SE)
0
10
20
30
40
50
60
70
80
90
100
N = 3 expts
% Ch
ange
in m
ean f
luores
cenc
e (m
ean +
SE)
0
10
20
30
40
50
60
70
80
90
100
N = 3 expts
% Ch
ange
in m
ean f
luores
cenc
e (m
ean +
SE)
0
10
20
30
40
50
60
70
80
90
100
% C
hang
e in m
ean f
luore
scen
ce
(mea
n + S
E)
0
10
20
30
40
50
60
70
80
90
100
FL GM-CSF T GM-CSF 1:1 2.5:10 1.25:10
p<0.001
p<0.001 p<0.001
N=1 exp
(TF1 Cells)
pSTAT5 Unstimulated Full Length Truncated 1:1 5/10 2.5/10 1.25/10
FL GM-CSF T GM-CSF 1:1 2.5:10 1.25:10
N = 3 expts
% C
hang
e in m
ean f
luore
scen
ce
(mea
n + S
E)
0
10
20
30
40
50
60
70
80
90
100
15 minutes
5 minutes
30 minutes
30 minute ratios
% C
hang
e in m
ean f
luore
scen
ce
(mea
n + S
E)
0
10
20
30
40
50
60
70
80
90
100
N = 3 expts
% C
hang
e in m
ean f
luore
scen
ce
(mea
n + S
E)
0
10
20
30
40
50
60
70
80
90
100
N = 3 expts
% C
hang
e in m
ean f
luore
scen
ce
(mea
n + S
E)
0
10
20
30
40
50
60
70
80
90
100
p<0.002
p<0.004 p<0.004
N=1 exp
(TF1 Cells)
% In
crea
se in
mea
n flo
ures
cenc
e (m
ean±
SE)
0
20
40
60
80
100
120
0
20
40
60
80
100
120
Truncated
Full Length
pJAK2
pSTAT5
GRAY = Untreated
BLUE = Truncated GM-CSF
RED = Full Length GM-CSF
N = 6 expts
N = 3 expts
Influence of Full Length and Truncated Human GM-CSF on Phosphorylation of JAK2 and STAT5 in Human CD34+ Cord Blood Cells
Effects of CD26/DPPIV -/- In Vivo on
Recovery from Stress
(radiation and drugs)
a
NS
a
a
NS
NS
a NS
NS
NS
NS NS
0
1000
2000
3000
4000
5000
6000
7000
0 12 24 36 48
Cell Lysate: 400 rads
PLASMA: 400 rads
PLASMA: 650 rads
Cell Lysate: 650 rads
Hours post irradiation
Rel
ativ
e Li
ght U
nits
DPPIV Activity in Plasma and Cell Lysates of Mice Pre- and Post- Radiation
CFU-GM Pr
ogen
itors
/fem
ur (t
hous
ands
)
0
5
10
15
20
25
30
35
40
45
Days Post 400cGy Radiation
D0 D7 D10 D21
1.7X
(<0.
04)
3.6X
(<0.
006)
3.9X
(<0.
03)
9.4X
(<0.
001)
6.9X
(<0.
002)
1.9X
a
WT
WT+Sitagliptin
CD26-/-
0
20
40
60
80
100
120
140 CFU-GM
Days Post 5FU
Prog
enito
rs/fe
mur
(tho
usan
ds)
D0 D7 D10 D21
3.0X
(<0.
001)
1.8X
(<0.
004)
9.5X
(<0.
001)
7.1X
(<0.
002)
ND
WT
WT+Sitagliptin
CD26-/-
Control
Sitagliptin (oral)
0
20
40
60
80
1 2 4 6
p=<0
.001 p=
<0.00
1 p=<0
.001
p=<0
.001
Primary Transplant (Competitive)
Months (post transplant)
% D
onor
(CD
45.2
) Chi
mer
ism
9
p=<0
.001
Effect of Oral Administration of DPP4 Inhibitor (Sitagliptin) to Lethally Irradiated Recipient Mice on Engraftment of Mouse Bone Marrow Cells
In-vivo inhibition to enhance engraftment of single-unit cord blood transplants in adults with
high-risk hematological malignancies
Farag, S.S., Srivastava, S., Messina-Graham, S., Schwartz, J., Nelson, R., Robertson, M., Abonour, R., Cornetta, K., Wood,
L., Secrest, A., Rojas, L., Strother, M.R., Jones, D., and Broxmeyer, H.E.
Stem Cells & Development 22:1007-1015, 2013
Sherif Farag M.D.
Sitagliptin: A clinical DPP-4 inhibitor
• Specific DPP-4 inhibitor • Only available PO • FDA approved for treatment of type 2 diabetes
mellitus (DM) • Extensively tested in healthy subjects
• Incretin stimulation of insulin release is glucose dependent; hypoglycemia not observed even at high doses
• PK and PD well characterized in healthy volunteers and patients with DM
Treatment Plan
Day of Transplantation -7 -6 -5 -4 -3 -2 -1 0 +1 +2
TBI (165 cGy bid) X X X X Cyclophosphamide (60 mg/kg/day)
X X
ATG (12.5 mg/kg/day)* X X X Sitagliptin (600 mg) X X X X UCB transplantation X
Filgrastim 5 μg/kg/day SC starting day +5 until ANC ≥2.0x109/l for 2 consecutive days
*ATG replaced by fludarabine 30 mg/m2 days -6 to -2 after first 11 patients to reduce risk of infections
Comparison to NYBC Data on engraftment of single UCB Units
Expected Outcome: < 80% engraftment by day 77 50% engraft by day ~28-30
Rubenstein et al. NEJM 1998, 351:2276
CD26 Inhibition
Days after transplantation
Cum
ulat
ive
inci
denc
e
of n
eutr
ophi
l eng
raftm
ent
Median days to engraftment 21 days
Activity of Plasma DPPIV (RCD CB Unit Transplant)*
* Maximum inhibition occurred 2-4 hrs after dosing, with DPPIV activity ≥80% of baseline by 16 hrs.
Pre-dose 0.5 1 2 4 8 12 16 24 2 4 8 16 24 2 4 8 16 24 2 4 8 16 24
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
Day -1 Day 0 Day +1 Day +2
Time after sitagliptin dose
Plas
ma
CD
26 A
ctiv
ity (%
of p
re-d
ose
leve
l)
Conclusions • DPP4 enzyme activity in patients receiving
sitagliptin was suboptimal • Opportunities to further improve the efficacy
of DPP-4 inhibition need to be explored: • Pharmacodynamic studies in transplant patients suggest
that more frequent doses of sitagliptin are required for sustained DPP-4 inhibition
• Longer duration of DPP-4 inhibition may be needed to take harness positive effects on hematopoeitic cytokines
• Modification in conditioning regimen
• Multicenter phase II trial sponsored by NHLBI is under development to confirm results
Influence of DPP4 Truncation on Negative Regulators of
Hematopoiesis
DEK • Mammalian nuclear phosphoprotein originally
identified as a fusion protein resulting from a t (6;9) translocation of a rare subtype of AML
Von Linderm et al Mol Cell Biol 12:1687, 1992
• Bears little resemblance to other known proteins, but is well conserved among higher eukaryotes
• In addition to its DNA-binding properties, it is found in association with mRNA splicing and export factors, as well as with spliced transcripts
• Plays an active role in maintaining higher order chromatin architecture
DEK • DEK can leave the cell, and in paracrine fashion, be
taken up by another cell, traffic to the nucleus of that cell and in bioactive form modulate global chromatin structure
David Markovitz and colleagues University of Michigan, Ann Arbor, MI
PNAS in press
DEK Regulates Hematopoietic Stem Engraftment and Progenitor Cell Proliferation
Broxmeyer, H.E., Kappes, F., Mor-Vakin, N., Legendre, M., Kinzfogl, J., Cooper, S., Hangoc, G.,
and Markovitz, D.M.
Stem Cells and Development 21: 1449-1454, 2012
0
10000
20000
30000
40000
Absolute Number of Progenitors / Femur
p=0.003
p=0.108 p=0.044
CFU-GM BFU-E CFU-GEMM
WT DEK (-/-)
0
5000
10000
15000
20000
Absolute Number of Progenitors /Spleen
p=0.006
p=0.001
p=0.129
CFU-GM BFU-E CFU-GEMM
0
20
40
60
80
100
Cycling: BM Progenitors (% S-Phase)
p=0.001 p=0.003 p=0.001
CFU-GM BFU-E CFU-GEMM 0
20
40
60
80
100
Cycling: Spleen Progenitors (% S-Phase)
p=0.001 p=0.001 p=0.001
CFU-GM BFU-E CFU-GEMM
DEK is myelosuppressive in vitro for colony formation by mouse CFU-GM,
BFU-E, and CFU-GEMM
0 10 20 30 40 50
CFU-GEMM
BFU-E
CFU-GM
Control
DEK (100nM)
Percent wells with colony
p<0.0001
p= 0.020
p= 0.059
0
20
40
60
80
100
1 2 4 6 1 3 5
Primary Mouse Recipients
Peripheral Blood Bone Marrow Peripheral Blood
Secondary Mouse Recipients WT
DEK (-/-)
Months: post transplant
NS NS p<0.002 p<0.04 p<0.002 p<0.002 p<0.002
% D
onor
Cel
l Chi
mer
ism
in
Com
petit
ive
Rep
opul
atin
g As
say
a) b)
A Role For DEK in Stem/Progenitor Cell Biology
Broxmeyer, H.E., Mor-Vaknin, N., Kappes, F., Legendre, M., Saha, A.K., Ou, X., O’Leary, H.A., Capitano, M., Cooper, S., and Markovitz, D.M.
Stem Cells in press
0 20 40 60 80
Control
FL DEK (50nM)
“ (10nM)
“ (1nM)
TR DEK (50nM)
“ (25nM)
FL DEK (50nM)+TR DEK (25nM)
“ + " (12.5nM)
“ + " (6.25nM)
0 25 50 75 100 125
Colony Formation
Exp #1 Exp #2
*, significantly different from control medium (p<0.05)
* *
* *
* ND
ND
ND
Influence of full length (FL) and DPP4-treated (=truncated, TR) DEK alone and in combination on 5x104 C57Bl/6 mouse BM cells/ml treated
with GM-CSF (Exp#1) or GM-CSF+SCF (Exp#2)
Potential Role for Dipeptidylpeptidase (DPP) 4 in Regulation of Many Different Cell and
Tissue Systems
Implications of DPP4 Modification of Proteins That Regulate Stem/Progenitor and More Mature Cell Types
Ou, X., O’Leary, H.A., and Broxmeyer, H.E. 2013 Blood in press
The Role of DPP4 in Hematopoiesis and Transplantation
O’Leary, H.A., Ou, X., and Broxmeyer, H.E. 2013 Current Opinions in Hematopoiesis (Hematology) in press
Chemokines Cytokines Peptide Species N-terminus Peptide Species N-terminus CXCL1 /GRO-α M APIAN… a,b Epo H APPRL… a,b CXCL2 /GRO-β/MIP-2α H APLAT… a,b Epo M APPRL… a,b CXCL4 /PF4 H EAEED… a,b GM-CSF H APARS… a,b CXCL5 /ENA-78 M APSSV… a,b GM-CSF M APTRS... a,b CXCL6/GCP2 H GPVSA… a,b G-CSF H ATPLG… a,b CXCL8/IL-8 H SAKEL… a,b G-CSF M VPLVT… a,b CXCL9/MIG H TPVVR… a,b IL-3 H APMTQ... a,b CXCL10/INP-10 H VPLSR… a,b IL-1 α H SAPFS… a,b CXCL10/INP-10 M IPLAR… a,b IL-1 β H APVRS… a,b CXCL11/I-TAC H IPLAR… a,b IL-1 α M SAPYT… a,b CXCL12/SDF-1 H KPVSL… a,b IL-1 β M VPIRQ… a,b CXCL12 (isoform α) M KPVSL… a,b IL-2 H APTSS… a,b CXCL12 (isoform β) M KPVSL… a,b IL-2 M APTSS… a,b CXCL12( isoform γ) M QPDAI… a,b IL-5 H IPTEI… a,b CCL2/MCP-1 H QPDAV… a,b IL-6 H VPPGE… a,b CCL2/MCP-1 M APYGA… a,b IL-6 M FPTSQ… a,b CCL3 /MIP-1α/LD78α M APLAA… a,b IL-8 (6-77) H SAEKL… a,b CCL3-L1/LD78β H APMGS… a,b IL-10 H SPGQG… a,b CCL4 /MIP-1β H APMGS… a,b IL-13 H GPVPP… a,b CCL4 /MIP-1β M APMGS… a,b IL-17B H QPRSP… a,b CCL5/RANTES H SPYSS… a,b IL-17A M AAIIP… a,b CCL5/RANTES M SPYGS… a,b IL-17C M DPPSW… a,b CCL7/MCP-3 H QPVGI… a,b IL-22 H APISS… a,b CCL7/MCP-3 M QPDGP… a,b IL-22 M LPVNT… a,b CCL8/MCP-2 H QPDSV… a,b IL-23 α H RAVPG… a,b CCL11/Eotaxin H GPASV… a,b IL-23 α M VPRSS… a,b CCL11/Eotaxin M HPGSI... a,b IL-27 α H FPRPP… a,b CCL12/MCP-5 M GPDAV... a,b IL-27 α M FPTDP… a,b CCL16/HCC-4/LEC/LCC-1/LMC H QPKVP… a,b IL-28A H VPVAR… a,b CCL19/CKβ11/MIP-3β/ELC/Exodus-3 M GANDA… a,b IL-28B H VPVAR… a,b CCL22/MDC/STCP-1 H GPYGA… a,b IL-28A M DPVPR… a,b CCL22/MDC/STCP-1 M GPYGA… a,b IL-28B M DPVPR… a,b CCL26/Eotaxin-3/MIP-4α M HPGSI… a,b IL-29 H GPVPT… a,b CCL27/CTACK/ILC/ESKINE M LPLPS… a,b
Chemokines/Cytokines with putative penultimate (Alanine/Proline) truncation site for DPP4
Modulatory Factors with putative penultimate (Alanine/Proline) truncation site for DPP4 (part 1)
Modulatory Factors Peptide Species N-terminus Peptide Species N-terminus Adipsin (propeptide) H PPRGR… a,b GDF-1 H DAEPV… a,b Adipsin (propeptide) M QPRGR…a,b GDF-3 H AAIPV…a,b α-1 microglobulin H GPVPT… a,b GDF-3 M AAISV… a,b α-1 microglobulin M DPAST… a,b GDF-5 H APLAT… a,b ANGPTL4 (isoform a) H GPVQS…a,b GDF-5 M APLAN… a,b ANGPTL4 (isoform b) H GPVQS…a,b GDF 6 H TAFAS… a,b ANGPTL6 H RAGAP…a,b GDF 6 M TAFAS… a,b BDNF (propeptide) H APMKE…a,b GDF-7 H TALAG… a,b BDNF (propeptide) M APMKE...a,b GDF-7 M TALAG… a,b bFGF H PALPE… a,b GDF-8 H GPVDL… a bFGF M PALPE… a,b GDNF (propeptide) H SPDKQ…a,b Bradykinin H RPPGF…a,b GDNF (propeptide) M SPDKQ… a,b Bradykinin M RPPGF… a,b GHRH H YADAI… a,b BMP-4 H SPKHH…a,b GLP-1 (7-36) H HAEGT… a,b BMP-4 M SPKHH…a,b GLP-2 H HADGS… a,b BMP-5 H AANKR… a,b GRP H VPLPA…a,b BMP-5 M AASKR… a,b GRP M APVST… a,b c1qTNF5 H SPPLD… a,b HCG α H APDVQ… a,b c1qTNF5 M SPPLD…a,b HCG α M LPDGD… a,b Chromogranin H LPVNS… a,b IGF-1 isoform 1 H GPETL… a,b Chromogranin M LPVNS…a,b IGF-1 isoform 2 H GPETL… a,b DKK 3 H APAPT…a,b IGF-1 isoform 3 H GPETL… a,b DNER H NPVPA… a,b IGF-1 isoform 4 H GPETL… a,b Enterostatin H APGPR... a,b IGF-1 isoform 1 M GPETL… a,b Enterostatin M APGPR…a,b IGF-1 isoform 2 M GPETL… a,b
IGF-1 isoform 3 M GPETL…a,b IGF-1 isoform 4 M GPETL… a,b IGF-1 isoform 5 M GPETL… a,b
Modulatory Factors with putative penultimate (Alanine/Proline) truncation site for DPP4 (part 2)
Modulatory Factors Peptide Species N-terminus Peptide Species N-terminus Inhibin alpha chain (propeptide) H HALGG…a,b RBP3 H GPTHL… a,b Inhibin alpha chain (propeptide) M HAVGG… a,b RBP3 M GPTHL…a,b Inhibin beta E chain H TPTCE… a,b Somatotropin isoform 1 H FPTIP… a,b Inhibin beta E chain M TPTCE… a,b Somatotropin isoform 2 H FPTIP… a,b Lactoferrin M KATTV… a,b Somatotropin isoform 3 H FPTIP… a,b leptin H VPIQK… a,b Somatotropin isoform 4 H FPTIP… a,b leptin M VPIQK… a,b Somatotropin M FPAMP… a,b LIF H SPLPI… a,b Transferrin H VPDKT… a,b LIF M SPLPI… a,b Transferrin M VPDKT… a,b LTα H LPGVG… a,b Trypsinogen H APFDD… a,b Neurotrophin-3 H YAEHK... a,b Vasostatin-1 H LPVNS… a,b Neurotrophin-3 M YAEHK… a,b Vasostatin-2 H LPVNS… a,b Notch 3 H APPCL… a,b VEGF A isoform i H APMAE… a,b Notch 3 M APPCL… a,b VEGF A isoform k H APMAE…a,b NPY H YPSKP… a,b VEGF A isoform l H APMAE… a,b NPY M YPSKP… a,b VEGF A isoform m H APMAE… a,b Oncostatin M H AAIGS… a,b VEGF A isoform n H APMAE… a,b Osteopontin H IPVKQ… a,b VEGF A isoform o H APMAE… a,b Osteopontin M LPVKV… a,b VEGF A isoform p H APMAE… a,b PDGFD M TPQRA…a,b VEGF A isoform 1 M APTTE…a,b Peptide YY H YPIKP… a,b VEGF A isoform 2 M APTTE… a,b Peptide YY M YPAKP… a,b VEGF A isoform 3 M APTTE… a,b Prolactin H LPICP…a,b Wnt 9b M AAYFG… a,b Prolactin M LPICS…a,b Wnt 10a H MPRSA... a,b
Wnt 10a M VPRSA… a,b
Peptides Species N-terminus Peptides Species N-terminus
CXCL1 H ASVAT… a,b ANGPT2 M YSNFR… a,b
CXCL3 H ASVVT… a,b BDNF H HSDPA… a,b
CXCL7 H SSTKG… a,b BDNF M HSDPA… a,b
CXCL7 M KSDGM… a,b DLL3 M HSFGP… a,b
CCL1 H KSMQV… a,b DLL4 M GSGIF… a,b
CCL1 M KSMLT… a,b DKK 3 M PSPTV… a,b
CCL20 H ASNFD… a,b FZD6 H HSLFT… a,b
CCL20 M ASNYD… a,b FZD6 M HSLFT… a,b
IL-3 M ASISG… a,b Glucagon M HSQGT… a,b
IL-17E M VSLRI… a,b Glucagon M HSQGT… a,b
IFN-β H MSYN… a,b GM2A H SSFSW… a,b
LTα M LSGVR… a,b Beta NGF H SSSHP… a,b
TGF-β1 H LSTCK… a,b Beta NGF M SSTHP… a,b
TGF-β1 M LSTCK… a,b PACAP (1-27) H HSDGI… a,b
TNF-β M LSGVR… a,b PACAP (1-38) H HSDGI… a,b
TNF (Membrane Form) H MSTES… a,b PDGFC M ESNLS… a,b
TNF (Membrane Form) M MSTES… a,b PDGFC H ESNLS… a,b
DEK H MSASA… a,b Wnt 8a M ASAWS… a,b
DEK M MSAAA… a,b Wnt 8b H WSVNN… a,b
Factors with putative truncation site (Serine) for DPP4
Potential Models for DPP4 Activity
Lab Members
Former Lab Members
Scott Cooper, M.S. Research Associate
Giao Hangoc, D.V.M. Research Associate
Charlie Mantel, B.S. Research Associate
Hal E Broxmeyer, Ph.D.
Man Ryul Lee, PhD Post Doc
Xuan Ou, Ph.D Post Doc
Heather O’Leary, Ph.D Post Doc
Sunanda Basu , Ph.D.. Sara Rohrabaugh Young-June Kim, Ph.D. Ying Liu , Ph.D.
Tammi Taylor, Ph.D. Timothy Campbell, M.D., Ph.D. Kent W. Christophersen II, PhD John Kinzfogl, Ph,D. Myung Kwan Han, PhD
Hee-Don Chae, Ph.D.
Steven Messina-Graham Grad Student
Xinxin Huang, PhD Post Doc
Maegan Capitano, Ph.D Post Doc
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