Protein phosphatase 1B dephosphorylates Rho guanine nucleotide dissociation inhibitor 1 and suppresses cancer cell migration and invasion

Cancer Lett. 2018 Mar 28:417:141-151. doi: 10.1016/j.canlet.2018.01.002. Epub 2018 Jan 5.

Abstract

Rho GTPases control a wide range of cellular processes, and their deregulation is associated with promotion of an aggressive and metastatic tumor phenotype in human cancers. Rho guanine nucleotide dissociation inhibitor 1 (RhoGDI1) plays a key role in regulating the activity of Rho GTPases. However, the underlying mechanisms are still unclear. In this study, we show that protein phosphatase 1B (PPM1B) interacts with RhoGDI1 and functions as its phosphatase. Ectopic expression of PPM1B results in dephosphorylation of RhoGDI1 and, thereby, abates the activation of RhoA, Rac1 and CDC42 by epidermal growth factor (EGF). PPM1B overexpression in Hs578T and SKBR3 human breast cancer cells decreases their motility and invasiveness in vitro and cancer metastasis in vivo. In contrast, knockdown of PPM1B in MCF-7 and MDA-MB-468 human breast cancer cells that express endogenous PPM1B enhances EGF-induced RhoGDI1 phosphorylation, activation of Rho GTPases, and cancer cell migration and invasion. Knockdown of RhoA or Rac1 by siRNA reverses the enhanced cell migration seen after PP1MB depletion. Collectively, these results indicate that PPM1B negatively regulates cancer cell motility and invasiveness through dephosphorylating RhoGDI1.

Keywords: Cancer; Migration; PPM1B; Rho GTPases; RhoGDI1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement*
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • MCF-7 Cells
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Phosphorylation
  • Protein Phosphatase 2C / genetics
  • Protein Phosphatase 2C / metabolism*
  • RNA Interference
  • Transplantation, Heterologous
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / metabolism*

Substances

  • rho Guanine Nucleotide Dissociation Inhibitor alpha
  • PPM1B protein, human
  • Protein Phosphatase 2C