title: A novel role of dipeptidyl peptidase 9 in epidermal growth factor signaling.
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 pathway-specific 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.
authors.affiliation: Centenary Institute, University of Sydney, NSW, Australia.
authors.forename: Tsun-Wen
authors.initials: TW
authors.lastname: Yao
authors.forename: Woo-Shin
authors.initials: WS
authors.lastname: Kim
authors.forename: Denise M T
authors.initials: DM
authors.lastname: Yu
authors.forename: George
authors.initials: G
authors.lastname: Sharbeen
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.forename: Pu
authors.initials: P
authors.lastname: Xia
authors.forename: Mark D
authors.initials: MD
authors.lastname: Gorrell
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004150:Dipeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000201:enzymology; D008113:Liver Neoplasms / Q000201:enzymology / Q000209:etiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C487997:DPP8 protein, human