Abstract
Dipeptidyl peptidase IV (DPP4), DPP8, DPP9, and fibroblast activation protein (FAP), the four proteases of the DPP4 gene family, have unique peptidase and extra-enzymatic activities that have been implicated in various diseases including cancers. We report here a novel role of DPP9 in regulating cell survival and proliferation through modulating molecular signaling cascades. Akt (protein kinase B) activation was significantly inhibited by human DPP9 overexpression in human hepatoma cells (HepG2 and Huh7) and human embryonic kidney cells (HEK293T), whereas extracellular signal-regulated kinases (ERK1/2) activity was unaffected, revealing a pathwayspecific effect. Interestingly, the inhibitory effect of DPP9 on Akt pathway activation was growth factor dependent. DPP9 overexpression caused apoptosis and significantly less epidermal growth factor (EGF)-mediated Akt activation in HepG2 cells. However, such inhibitory effect was not observed in cells stimulated with other growth factors, including connective tissue growth factor, hepatic growth factor, insulin or platelet-derived growth factor-BB. The effect of DPP9 on Akt did not occur when DPP9 enzyme activity was ablated by either mutagenesis or inhibition. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a major downstream effector of Ras. We found that DPP9 and DPP8, but not DPP4 or FAP, associate with H-Ras, a key signal molecule of the EGF receptor signaling pathway. These findings suggest an important signaling role of DPP9 in the regulation of survival and proliferation pathways.
| Original language | English |
|---|---|
| Pages (from-to) | 948-959 |
| Number of pages | 12 |
| Journal | Molecular Cancer Research |
| Volume | 9 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2011 Jul 1 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Oncology
- Cancer Research
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A novel role of dipeptidyl peptidase 9 in epidermal growth factor signaling. / Yao, Tsun Wen; Kim, Woo Shin; Yu, Denise M.T.; Sharbeen, George; McCaughan, Geoffrey W.; Choi, Kang Yell; Xia, Pu; Gorrell, Mark D.
In: Molecular Cancer Research, Vol. 9, No. 7, 01.07.2011, p. 948-959.Research output: Contribution to journal › Article
TY - JOUR
T1 - A novel role of dipeptidyl peptidase 9 in epidermal growth factor signaling
AU - Yao, Tsun Wen
AU - Kim, Woo Shin
AU - Yu, Denise M.T.
AU - Sharbeen, George
AU - McCaughan, Geoffrey W.
AU - Choi, Kang Yell
AU - Xia, Pu
AU - Gorrell, Mark D.
PY - 2011/7/1
Y1 - 2011/7/1
N2 - Dipeptidyl peptidase IV (DPP4), DPP8, DPP9, and fibroblast activation protein (FAP), the four proteases of the DPP4 gene family, have unique peptidase and extra-enzymatic activities that have been implicated in various diseases including cancers. We report here a novel role of DPP9 in regulating cell survival and proliferation through modulating molecular signaling cascades. Akt (protein kinase B) activation was significantly inhibited by human DPP9 overexpression in human hepatoma cells (HepG2 and Huh7) and human embryonic kidney cells (HEK293T), whereas extracellular signal-regulated kinases (ERK1/2) activity was unaffected, revealing a pathwayspecific effect. Interestingly, the inhibitory effect of DPP9 on Akt pathway activation was growth factor dependent. DPP9 overexpression caused apoptosis and significantly less epidermal growth factor (EGF)-mediated Akt activation in HepG2 cells. However, such inhibitory effect was not observed in cells stimulated with other growth factors, including connective tissue growth factor, hepatic growth factor, insulin or platelet-derived growth factor-BB. The effect of DPP9 on Akt did not occur when DPP9 enzyme activity was ablated by either mutagenesis or inhibition. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a major downstream effector of Ras. We found that DPP9 and DPP8, but not DPP4 or FAP, associate with H-Ras, a key signal molecule of the EGF receptor signaling pathway. These findings suggest an important signaling role of DPP9 in the regulation of survival and proliferation pathways.
AB - Dipeptidyl peptidase IV (DPP4), DPP8, DPP9, and fibroblast activation protein (FAP), the four proteases of the DPP4 gene family, have unique peptidase and extra-enzymatic activities that have been implicated in various diseases including cancers. We report here a novel role of DPP9 in regulating cell survival and proliferation through modulating molecular signaling cascades. Akt (protein kinase B) activation was significantly inhibited by human DPP9 overexpression in human hepatoma cells (HepG2 and Huh7) and human embryonic kidney cells (HEK293T), whereas extracellular signal-regulated kinases (ERK1/2) activity was unaffected, revealing a pathwayspecific effect. Interestingly, the inhibitory effect of DPP9 on Akt pathway activation was growth factor dependent. DPP9 overexpression caused apoptosis and significantly less epidermal growth factor (EGF)-mediated Akt activation in HepG2 cells. However, such inhibitory effect was not observed in cells stimulated with other growth factors, including connective tissue growth factor, hepatic growth factor, insulin or platelet-derived growth factor-BB. The effect of DPP9 on Akt did not occur when DPP9 enzyme activity was ablated by either mutagenesis or inhibition. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a major downstream effector of Ras. We found that DPP9 and DPP8, but not DPP4 or FAP, associate with H-Ras, a key signal molecule of the EGF receptor signaling pathway. These findings suggest an important signaling role of DPP9 in the regulation of survival and proliferation pathways.
UR - http://www.scopus.com/inward/record.url?scp=79960661852&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960661852&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-10-0272
DO - 10.1158/1541-7786.MCR-10-0272
M3 - Article
C2 - 21622624
AN - SCOPUS:79960661852
VL - 9
SP - 948
EP - 959
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 7
ER -