Maspin controls mammary tumor cell migration through inhibiting Rac1 and Cdc42, but not the RhoA GTPase

Heidi Y. Shi, Lewis Joe Stafford, Zhisheng Liu, Mingyao Liu, Ming Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Rac1 and Cdc42 are members of the Rho family of small GTPases that play essential roles in diverse cellular functions, including cell migration. The activities of these Rho family proteins are controlled by growth factor receptor activation and cell-ECM interactions. Here, we show that maspin, a well-documented tumor suppressor gene, also controls cell motility through inhibiting Rac1/Cdc42 activity. Using the GST-PAK and GST-Rho binding protein pull-down assays for GTP-bound Rac1, Cdc42, and RhoA, we showed that treatment of MDA-MB-231 tumor cells with recombinant maspin for a short time period significantly inhibited the activity of Rac1 and Cdc42, but not RhoA. The reactive site loop (RSL) within maspin protein is the functional domain involved in the inhibition. Maspin mutants with the RSL deleted or a point mutation in the RSL region lost their inhibitory activity. We further examined the ability of maspin to inhibit Rac1- and Cdc42-mediated signaling pathways and transcription factors. Treatment of MDA-MB-231 cells with maspin led to the inhibition of JNK kinase activity as assayed by immuno-kinase assays. In addition, the AP-1 transcription activity downstream of JNK kinase pathway was also reduced. Together, we have identified Rac1 and Cdc42 as the downstream targets that mediate the inhibition of mammary tumor cell migration by maspin.

Original languageEnglish (US)
Pages (from-to)338-346
Number of pages9
JournalCell motility and the cytoskeleton
Volume64
Issue number5
DOIs
StatePublished - May 1 2007

Keywords

  • Cell migration
  • Invasion and metastasis
  • MDA-MB-231 mammary tumors
  • Maspin
  • Rho GTPase

ASJC Scopus subject areas

  • Structural Biology
  • Cell Biology

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