title: CD97 inhibits cell migration in human fibrosarcoma cells by modulating TIMP-2/MT1- MMP/MMP-2 activity--role of GPS autoproteolysis and functional cooperation between the N- and C-terminal fragments.
abstract: CD97 is a tumor-associated adhesion-class G-protein-coupled receptor involved in modulating cell migration. Adhesion-class G-protein-coupled receptors are characterized by proteolytic cleavage at a G-protein-coupled receptor proteolysis site (GPS) into an N-terminal fragment (NTF) and a C-terminal fragment (CTF), which remain associated noncovalently. The molecular mechanism and the role of GPS proteolysis in CD97-modulated cell migration are not completely understood. We report here that CD97 expression in HT1080 fibrosarcoma cells enhanced tissue inhibitor of metalloproteinase-2 secretion, leading to reduced membrane type 1 matrix metalloproteinase and matrix metalloproteinase 2 activities. This, in turn, impaired cell migration and invasion in vitro and lung macrometastasis in vivo. CD97 expression also upregulated the expression of integrins, promoting cell adhesion. Importantly, these cellular functions absolutely required the presence of both the NTF and the CTF of CD97, confirming functional cooperation between the two receptor subunits. CD97 gene knockdown reversed these phenotypic changes. We conclude that GPS proteolysis and the functional interplay between the NTF and the CTF are indispensible for CD97 to inhibit HT1080 cell migration by suppressing matrix metalloproteinase activity.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Cheng-Chih
authors.initials: CC
authors.lastname: Hsiao
authors.forename: Wen-Chih
authors.initials: WC
authors.lastname: Wang
authors.forename: Wan-Lin
authors.initials: WL
authors.lastname: Kuo
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
authors.forename: Jörg
authors.initials: J
authors.lastname: Hamann
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Lin
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002633:Chemotaxis; D017077:Culture Media, Conditioned; D004789:Enzyme Activation; D005260:Female; D005354:Fibrosarcoma / Q000201:enzymology / Q000473:pathology* / Q000556:secondary; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000235:genetics; D008175:Lung Neoplasms / Q000201:enzymology / Q000556:secondary; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D053517:Matrix Metalloproteinase 15 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
chemical_list: C095004:ADGRE5 protein, human; D015703:Antigens, CD; D017077:Culture Media, Conditioned; D016023:Integrins; C507098:MMP15 protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D053517:Matrix Metalloproteinase 15; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: CD97; adhesion-class G-protein-coupled receptors (adhesion-GPCRs); cell migration; matrix metalloproteinases; metastasis