Regulation of vesicle transport and cell motility by golgi-localized dbs

Ethan R. Fitzpatrick, Tinghui Hu, Bryan T. Ciccarelli, Ian Whitehead

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

DBS/MCF2L has been recently identified as a risk locus for osteoarthritis. It encodes a guanine nucleotide exchange factor (Dbs) that has been shown to regulate both normal and tumor cell motility. In the current study, we have determined that endogenous Dbs is predominantly expressed as 2 isoforms, a 130 kDa form (Dbs-130) that is localized to the Golgi complex, and an 80 kDa form (Dbs-80) that is localized to the endoplasmic reticulum (ER). We have previously described an inhibitor that binds to the RhoGEF domain of Dbs and blocks its transforming activity. Here we show that the inhibitor localizes to the Golgi, where it specifically interacts with Dbs-130. Inhibition of endogenous Dbs130 activity is associated with reduced levels of activated Cdc42, enlarged Golgi, and resistance to Brefeldin A-mediated Golgi dispersal, suggesting a role for Dbs in vesicle transport. Cells treated with the inhibitor exhibit normal protein transport from the ER to the Golgi, but are defective in transport from the Golgi to the plasma membrane. Inhibition of Dbs-130 in MDA-MB-231 human breast tumor cells limits motility in both transwell and wound healing assays, but appears to have no effect on the organization of the microtubule cytoskeleton. The reduced motility is associated with a failure to reorient the Golgi toward the leading edge. This is consistent with the Golgi localization, and suggests that the Dbs-130 regulates aspects of the secretory pathway that are required to support cell polarization during directed migration.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalSmall GTPases
Volume5
Issue number4
DOIs
StatePublished - Dec 13 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology

Keywords

  • Breast cancer
  • Cell motility
  • Dbs
  • Golgi complex
  • Guanine nucleotide exchange factor
  • MCF2L
  • Osteoarthritis
  • Rho

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