Nm23-H1 regulates contact inhibition of locomotion, which is affected by ephrin-B1.
Contact inhibition of locomotion (CIL) is the process by which cells stop the continual migration in the same direction after collision with another cell. Highly invasive malignant cells exhibit diminished CIL when they contact stromal cells, which allows invasion of the tissue by tumors. We show that Nm23-H1 is essential for the suppression of Rac1 through inactivation of Tiam1 at the sites of cell-cell contact, which plays a pivotal role in CIL. U87MG cells show CIL when they contact normal glia. In spheroid confrontation assays U87MG cells showed only limited invasion of the glial population, but reduction of Nm23-H1 expression in U87MG cells abrogated CIL resulting in invasion. In U87MG cells, Nm23-H1 is translocated to the sites of contact with glia through association with α-catenin and N-cadherin. Mutants of Nm23-H1, which lacked the binding ability with Tiam1, or α-catenin did not restore CIL. Moreover, the expression of ephrin-B1 in tumor cells disrupted CIL and promoted invasion. As one mechanism, ephrin-B1 inhibits the association of Nm23-H1 with Tiam1, which contributes for activation of Rac1. These results indicate a novel function of Nm23-H1 to control CIL, and its negative regulation by ephrin-B1.
Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. mastanak@med.akita-u.ac.jp
Masamitsu
M
Tanaka
Sei
S
Kuriyama
Namiko
N
Aiba
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D003260:Contact Inhibition; D036387:Ephrin-B1 / Q000737:chemistry / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D054778:NM23 Nucleoside Diphosphate Kinases / Q000737:chemistry / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D051178:alpha Catenin / Q000378:metabolism
D015820:Cadherins; D036387:Ephrin-B1; D020662:Guanine Nucleotide Exchange Factors; D054778:NM23 Nucleoside Diphosphate Kinases; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D051178:alpha Catenin; C517938:NME1 protein, human; C580701:Nm23-H1 protein, rat