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The rho-specific guanine nucleotide exchange factor Dbs regulates breast cancer cell migration

Zhuoming Liu1, Homer C Adams, Ian P Whitehead

  • 1Department of Microbiology and Molecular Genetics and the New Jersey Medical School-University Hospital Cancer Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07101-1709, USA.

The Journal of Biological Chemistry
|April 16, 2009
PubMed

Insights

Dbs protein regulates breast cancer cell movement by activating Cdc42 and Rac1 pathways. This pathway involves Ack1, p130Cas, and Crk, impacting cell motility and tyrosine phosphorylation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Dbs (Dbl-like protein) is a Rho-specific guanine nucleotide exchange factor (RhoGEF).
  • Dbs regulates neurotrophin-3-induced cell migration in Schwann cells.
  • Rho GTPases like Cdc42 and Rac1 are crucial for cell motility.

Purpose of the Study:

  • To investigate the role of Dbs in regulating cell motility in human breast epithelial cells.
  • To elucidate the specific Rho GTPases and downstream signaling pathways involved in Dbs-mediated cell motility.
  • To determine if Dbs plays a role in human breast cancer cell movement.

Main Methods:

  • Stable expression of onco- or proto-Dbs in T47D cells.
  • Small interfering RNA (siRNA) mediated suppression of Cdc42, Rac1, Ack1, p130(Cas), and Crk.
  • Analysis of cell motility, GTPase activation, and tyrosine phosphorylation of focal adhesion kinase (FAK) and p130(Cas).

Main Results:

  • Dbs activates Cdc42 and Rac1 in T47D cells, enhancing cell motility, particularly on collagen I.
  • Dbs-enhanced motility correlates with increased tyrosine phosphorylation of FAK and p130(Cas), and Crk.p130(Cas) complex formation.
  • Suppression of Cdc42, Ack1, p130(Cas), or Crk attenuates Dbs-induced Rac1 activation and cell motility.
  • Endogenous Dbs suppression reduces motility in T47D and MDA-MB-231 cells, correlating with decreased Cdc42 activity.

Conclusions:

  • Dbs activates a signaling cascade involving Cdc42, Ack1, and the Crk.p130(Cas) complex to promote Rac1 activation and cell motility.
  • Dbs plays a significant role in supporting the movement of human breast cancer cells.
  • Targeting the Dbs-Cdc42-Rac1 pathway may offer therapeutic strategies for breast cancer treatment.

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