title: TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling.
abstract: We recently reported that hNSCs (human neural stem cells) have the interesting characteristic of migration towards an intracranial glioma. However, the molecules and mechanisms responsible for tumour tropism are unclear. In the present study, we used microarray and proteomics analyses to identify a novel chemoattractant molecule, TIMP-1 (tissue inhibitor of metalloproteinase-1), secreted from human brain tumour tissues. We demonstrate that TIMP-1 significantly enhances hNSC adhesion and migration in a cell culture system. These effects were critically dependent on CD63, as shRNA-mediated ablation of CD63 expression attenuated the response. TIMP-1 significantly increased the number of FAs (focal adhesions) and cytoskeletal reorganization for cell migration in hNSCs, whereas knockdown of CD63 resulted in decreased hNSC spreading, FAs and migration, even after TIMP-1 treatment. In addition, TIMP-1 binding to CD63 activated β1 integrin-mediated signalling through Akt and FAK phosphorylation, leading to pattern changes in distribution of vinculin and F-actin (filamentous actin). Furthermore, inactivation of β1 integrin by use of a blocking antibody or inhibition of PI3K (phosphoinositide 3-kinase) signalling impaired the migration of hNSCs towards TIMP-1. Collectively, our results underline TIMP-1 as a novel and effective key regulator of CD63 and β1 integrin-mediated signalling, which regulates hNSC adhesion and migration.
authors.forename: Soo Youn
authors.initials: SY
authors.lastname: Lee
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Kim
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Cho
authors.forename: Hyun Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Shin
authors.forename: Jeong Yong
authors.initials: JY
authors.lastname: Jeon
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Kausar
authors.affiliation: ∥Department of Medical Genetics, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Seon Yong
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: ¶Division of Molecular Life Science, Hanyang University, Ansan, Korea.
authors.forename: Young Seek
authors.initials: YS
authors.lastname: Lee
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Lee
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D002633:Chemotaxis; D003599:Cytoskeleton / Q000378:metabolism; D020868:Gene Silencing; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D019012:Integrin beta1 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D060149:Tetraspanin 30 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C554586:CD63 protein, human; D019012:Integrin beta1; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C560822:TIMP1 protein, human; D060149:Tetraspanin 30; D019715:Tissue Inhibitor of Metalloproteinase-1