PtdIns(3,4,5)P3 -dependent rac exchanger 1 (PREX1) rac-guanine nucleotide exchange factor (GEF) activity promotes breast cancer cell proliferation and tumor growth via activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling

Heng-Jia Liu, Lisa M. Ooms, Nuthasuda Srijakotre, Joey Man, Jessica Vieusseux, JoAnne E. Waters, Yue Feng, Charles G. Bailey, John E. J. Rasko, John T. Price, Christina A. Mitchell

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8 Citations (Scopus)

Abstract

PtdIns(3,4,5)P3 -dependent Rac exchanger 1 (PREX1) is a Rac-guanine nucleotide exchange factor (GEF) overexpressed in a significant proportion of human breast cancers that integrates signals from upstream ErbB2/3 and CXCR4 membrane surface receptors. However, the PREX1 domains that facilitate its oncogenic activity and downstream signaling are not completely understood. We identify that ERK1/2 MAPK acts downstream of PREX1 and contributes to PREX1-mediated anchorage-independent cell growth. PREX1 overexpression increased but its shRNA knockdown decreased ERK1/2 phosphorylation in response to EGF/IGF-1 stimulation, resulting in induction of the cell cycle regulators cyclin D1 and p21WAF1/CIP1 . PREX1-mediated ERK1/2 phosphorylation, anchorage-independent cell growth, and cell migration were suppressed by inhibition of MEK1/2/ERK1/2 signaling. PREX1 overexpression reduced staurosporine-induced apoptosis whereas its shRNA knockdown promoted apoptosis in response to staurosporine or the anti-estrogen drug tamoxifen. Expression of wild-type but not GEF-inactive PREX1 increased anchorage-independent cell growth. In addition, mouse xenograft studies revealed that expression of wild-type but not GEF-dead PREX1 resulted in the formation of larger tumors that displayed increased phosphorylation of ERK1/2 but not AKT. The impaired anchorage-independent cell growth, apoptosis, and ERK1/2 signaling observed in stable PREX1 knockdown cells was restored by expression of wild-type but not GEF-dead-PREX1. Therefore, PREX1-Rac-GEF activity is critical for PREX1-dependent anchorage-independent cell growth and xenograft tumor growth and may represent a possible therapeutic target for breast cancers that exhibit PREX1 overexpression.

The full article is found on the Journal of Biological Chemistry website: http://www.jbc.org/content/291/33/17258.full.pdf
Original languageEnglish
Pages (from-to)17258-17270
Number of pages13
JournalThe Journal of Biological Chemistry
Volume291
Issue number33
DOIs
Publication statusPublished - 12 Aug 2016

Keywords

  • breast cancer
  • cell migration
  • cell proliferation
  • cell signaling
  • ERK
  • guanine nucleotide exchange factor (GEF)

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