Integrin alpha 7 interacts with high temperature requirement A2 (HtrA2) to induce prostate cancer cell death.
Integrins are a family of receptors for extracellular matrix proteins that have critical roles in human tissue development. Previous studies identified down-regulation and/or mutations of integrin alpha7 (ITGA7) in prostate cancer, liver cancer, soft tissue leiomyosarcoma, and glioblastoma multiforme. Here we report that expression of ITGA7 induced apoptosis in the human prostate cancer cell lines PC3 and DU145. Yeast two-hybrid analysis revealed that the C-terminus of ITGA7 interacts with high temperature requirement A2 (HtrA2), a serine protease with a critical role in apoptosis. Expression of ITGA7 increases the protease activity of HtrA2 both in vitro and in vivo. Deletion of the HtrA2 interaction domain abrogates the cell death activity of ITGA7, whereas down-regulation of HtrA2 dramatically reduced cell death mediated by ITGA7. In addition, site-directed protease-null mutant HtrA2S306A expression blocked apoptosis induced by ITGA7. Interestingly, interaction between ITGA7 and its ligand laminin 2 appears to protect against cell death, since depleting laminin beta2 with a small-interfering RNA significantly exacerbated apoptosis induced by ITGA7 expression. This report provides a novel insight into the mechanism by which ITGA7 acts as a tumor suppressor.
Zhu
Ze-Hua
ZH
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Yu
Yan P
YP
Zheng
Zhong-Liang
ZL
Song
Yang
Y
Xiang
Guo-Sheng
GS
Nelson
Joel
J
Michalopoulos
George
G
Luo
Jian-Hua
JH
D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D039001:Integrin alpha Chains / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D015703:Antigens, CD; D039001:Integrin alpha Chains; D007797:Laminin; D024101:Mitochondrial Proteins; C085725:integrin alpha7; C058783:laminin beta2; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2