A novel role of dipeptidyl peptidase 9 in epidermal growth factor signaling

Tsun Wen Yao, Woo Shin Kim, Denise M.T. Yu, George Sharbeen, Geoffrey W. McCaughan, Kang-Yell Choi, Pu Xia, Mark D. Gorrell

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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 languageEnglish
Pages (from-to)948-959
Number of pages12
JournalMolecular Cancer Research
Volume9
Issue number7
DOIs
Publication statusPublished - 2011 Jul 1

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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Epidermal Growth Factor
Intercellular Signaling Peptides and Proteins
Hep G2 Cells
Peptide Hydrolases
Fibroblasts
Phosphatidylinositol 3-Kinase
Dipeptidyl Peptidase 4
Connective Tissue Growth Factor
Proto-Oncogene Proteins c-akt
Mitogen-Activated Protein Kinase 1
Epidermal Growth Factor Receptor
Mutagenesis
Hepatocellular Carcinoma
Cell Survival
Proteins
Cell Proliferation
Insulin
Apoptosis
Kidney

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Yao, T. W., Kim, W. S., Yu, D. M. T., Sharbeen, G., McCaughan, G. W., Choi, K-Y., ... Gorrell, M. D. (2011). A novel role of dipeptidyl peptidase 9 in epidermal growth factor signaling. Molecular Cancer Research, 9(7), 948-959. https://doi.org/10.1158/1541-7786.MCR-10-0272
Yao, Tsun Wen ; Kim, Woo Shin ; Yu, Denise M.T. ; Sharbeen, George ; McCaughan, Geoffrey W. ; Choi, Kang-Yell ; Xia, Pu ; Gorrell, Mark D. / A novel role of dipeptidyl peptidase 9 in epidermal growth factor signaling. In: Molecular Cancer Research. 2011 ; Vol. 9, No. 7. pp. 948-959.
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Yao, TW, Kim, WS, Yu, DMT, Sharbeen, G, McCaughan, GW, Choi, K-Y, Xia, P & Gorrell, MD 2011, 'A novel role of dipeptidyl peptidase 9 in epidermal growth factor signaling', Molecular Cancer Research, vol. 9, no. 7, pp. 948-959. https://doi.org/10.1158/1541-7786.MCR-10-0272

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 journalArticle

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