The Sprouty-related protein, Spred, inhibits cell motility, metastasis, and Rho-mediated actin reorganization.
Sprouty and the Sprouty-related protein, Spred (Sprouty-related Ena/vasodilator-stimulated phosphoprotein homology-1 (EVH1) domain-containing protein), inhibit Ras-dependent extracellular signal-regulated kinase (ERK) signaling induced by a variety of growth factors. Since Sprouty proteins have been shown to inhibit not only ERK activation but also cell migration, we postulated that Spreds also inhibit cellular migration. Using stably highly metastatic LM8 cells infected with the Spred1-Sendai virus vector, we demonstrated that Spred1 inhibits the metastasis of LM8 cells in nude mice. Spred1 overexpression also inhibited migration of cells in vitro in response to chemokines, CCL19 and CCL21. We also found that Spred1 overexpression dissolved actin-stress fibers. Both EVH1 domain and C-terminal Sprouty-related domain were required for actin reassembly. Spred1 and Spred2 suppressed constitutively activated RhoA (V14RhoA)-induced stress fiber formation and serum response factor activation. Spred1 bound to activated RhoA, but not cdc42 and Rac. Spred1 also inhibited chemokine-induced RhoA activation and active RhoA-induced Rho-kinase activation. These data suggest that Spreds are key regulators of RhoA-mediated cell motility and signal transduction. Furthermore, our study suggests that the induction of Spreds could be a novel strategy for preventing cancer cell metastasis.
Miyoshi
Kanta
K
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Wakioka
Toru
T
Nishinakamura
Hitomi
H
Kamio
Masaki
M
Yang
Lu
L
Inoue
Makoto
M
Hasegawa
Mamoru
M
Yonemitsu
Yoshikazu
Y
Komiya
Setsuro
S
Yoshimura
Akihiko
A
D000199:Actins / Q000737:chemistry*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D022502:Stress Fibers / Q000187:drug effects; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000494:pharmacology*
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D012097:Repressor Proteins; C433763:Spred1 protein, mouse; C433764:Spred2 protein, mouse; D020742:rhoA GTP-Binding Protein