Interaction of integrin-linked kinase and miniature chromosome maintenance 7-mediating integrin {alpha}7 induced cell growth suppression.
Mutation of integrin alpha7 (ITGA7) was previously identified in multiple human malignancies. Restoration of ITGA7 expression in prostate cancer and leiomyosarcoma cell lines suppressed tumor growth and cell motility both in vitro and in vivo. In this study, we showed that integrin-linked kinase (ILK) binds with miniature chromosome maintenance 7 (MCM7), a DNA replication licensing protein. A 58-amino acid ILK binding motif was identified in the NH(2)-terminus of MCM7. The expression of ITGA7 induced the phosphorylation of MCM7. Knocking down of ILK abrogated ITGA7-induced MCM7 phosphorylation. ANK, the dominant-negative mutant of ILK, also blocked the phosphorylation of MCM7 induced by ITGA7. The phosphorylation of MCM7 reduced MCM7 chromatin association and inhibited cell growth. A MCM7 mutant that does not bind with ILK did not respond to ITGA7 stimulation, and behaved similarly to a dominant MCM7-negative mutant and neutralized the effect of ITGA7. We conclude that ILK interaction with MCM7 and MCM7 phosphorylation may be a critical event in ITGA7 signaling pathway, leading to tumor suppression.
Han
Yu-Chen
YC
Departments of Pathology and Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Yu
Yan P
YP
Nelson
Joel
J
Wu
Chuanyue
C
Wang
Hui
H
Michalopoulos
George K
GK
Luo
Jian-Hua
JH
D015703:Antigens, CD / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D039001:Integrin alpha Chains / Q000096:biosynthesis; D008297:Male; D064168:Minichromosome Maintenance Complex Component 7; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099200:Scaffold Protein ILK
D015703:Antigens, CD; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D039001:Integrin alpha Chains; D064168:Minichromosome Maintenance Complex Component 7; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C085725:integrin alpha7; C101624:MCM7 protein, human
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