Back to Search
Start Over
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
- Source :
- The Journal of biological chemistry. 291(33)
- Publication Year :
- 2016
-
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 p21(WAF1/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.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Cyclin-Dependent Kinase Inhibitor p21
Cell signaling
MAP Kinase Signaling System
MAP Kinase Kinase 1
Mice, Nude
Breast Neoplasms
Biology
Biochemistry
03 medical and health sciences
Mice
Animals
Guanine Nucleotide Exchange Factors
Humans
Molecular Biology
Protein kinase B
Cell Proliferation
Mitogen-Activated Protein Kinase 1
Mice, Inbred BALB C
Mitogen-Activated Protein Kinase 3
Cell growth
Cell Biology
Cell cycle
PREX1
Cell biology
Gene Expression Regulation, Neoplastic
Tamoxifen
030104 developmental biology
Cancer research
MCF-7 Cells
Phosphorylation
Female
Guanine nucleotide exchange factor
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- ISSN :
- 1083351X
- Volume :
- 291
- Issue :
- 33
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....ff2547ae43968a546a378528d7d5bbdf