The Sprouty-related protein, Spred, inhibits cell motility, metastasis, and Rho-mediated actin reorganization

Kanta Miyoshi, Toru Wakioka, Hitomi Nishinakamura, Masaki Kamio, Lu Yang, Makoto Inoue, Mamoru Hasegawa, Yoshikazu Yonemitsu, Setsuro Komiya, Akihiko Yoshimura

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)

Abstract

Sprouty and the Sprouty-related protein, Spred (Sprouty-related Ena/vasodilator-stimulated phospho-protein 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.

Original languageEnglish
Pages (from-to)5567-5576
Number of pages10
JournalOncogene
Volume23
Issue number33
DOIs
Publication statusPublished - 2004 Jul 22
Externally publishedYes

Keywords

  • ERK
  • Metastasis
  • Migration
  • Rho
  • Signal transduction
  • Sprouty

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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