title: αvβ8 integrin interacts with RhoGDI1 to regulate Rac1 and Cdc42 activation and drive glioblastoma cell invasion.
abstract: The malignant brain cancer glioblastoma multiforme (GBM) displays invasive growth behaviors that are regulated by extracellular cues within the neural microenvironment. The adhesion and signaling pathways that drive GBM cell invasion remain largely uncharacterized. Here we use human GBM cell lines, primary patient samples, and preclinical mouse models to demonstrate that integrin αvβ8 is a major driver of GBM cell invasion. β8 integrin is overexpressed in many human GBM cells, with higher integrin expression correlating with increased invasion and diminished patient survival. Silencing β8 integrin in human GBM cells leads to impaired tumor cell invasion due to hyperactivation of the Rho GTPases Rac1 and Cdc42. β8 integrin coimmunoprecipitates with Rho-GDP dissociation inhibitor 1 (RhoGDI1), an intracellular signaling effector that sequesters Rho GTPases in their inactive GDP-bound states. Silencing RhoGDI1 expression or uncoupling αvβ8 integrin-RhoGDI1 protein interactions blocks GBM cell invasion due to Rho GTPase hyperactivation. These data reveal for the first time that αvβ8 integrin, via interactions with RhoGDI1, regulates activation of Rho proteins to promote GBM cell invasiveness. Hence targeting the αvβ8 integrin-RhoGDI1 signaling axis might be an effective strategy for blocking GBM cell invasion.
authors.affiliation: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Steve B
authors.initials: SB
authors.lastname: Reyes
authors.forename: Anjana S
authors.initials: AS
authors.lastname: Narayanan
authors.forename: Hye Shin
authors.initials: HS
authors.lastname: Lee
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Tchaicha
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Tolias
authors.forename: Joseph H
authors.initials: JH
authors.lastname: McCarty
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013238:Stereotaxic Techniques; D020764:cdc42 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: C569638:ARHGDIA protein, human; D016023:Integrins; D020033:Protein Isoforms; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; C403414:integrin alphavbeta8; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein