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

Research output: Contribution to journalArticleResearchpeer-review

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
JournalJournal 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)

Cite this

@article{d1049897713d41bda4bfbd3b71d7d6ed,
title = "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",
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",
keywords = "breast cancer, cell migration, cell proliferation, cell signaling, ERK, guanine nucleotide exchange factor (GEF)",
author = "Heng-Jia Liu and Ooms, {Lisa M.} and Nuthasuda Srijakotre and Joey Man and Jessica Vieusseux and Waters, {JoAnne E.} and Yue Feng and Bailey, {Charles G.} and Rasko, {John E. J.} and Price, {John T.} and Mitchell, {Christina A.}",
year = "2016",
month = "8",
day = "12",
doi = "10.1074/jbc.M116.743401",
language = "English",
volume = "291",
pages = "17258--17270",
journal = "Journal of Biological Chemistry",
issn = "1083-351X",
publisher = "American Society for Biochemistry and Molecular Biology",
number = "33",

}

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

In: Journal of Biological Chemistry, Vol. 291, No. 33, 12.08.2016, p. 17258-17270.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 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

AU - Liu, Heng-Jia

AU - Ooms, Lisa M.

AU - Srijakotre, Nuthasuda

AU - Man, Joey

AU - Vieusseux, Jessica

AU - Waters, JoAnne E.

AU - Feng, Yue

AU - Bailey, Charles G.

AU - Rasko, John E. J.

AU - Price, John T.

AU - Mitchell, Christina A.

PY - 2016/8/12

Y1 - 2016/8/12

N2 - 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

AB - 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

KW - breast cancer

KW - cell migration

KW - cell proliferation

KW - cell signaling

KW - ERK

KW - guanine nucleotide exchange factor (GEF)

UR - http://www.scopus.com/inward/record.url?scp=84981340864&partnerID=8YFLogxK

U2 - 10.1074/jbc.M116.743401

DO - 10.1074/jbc.M116.743401

M3 - Article

VL - 291

SP - 17258

EP - 17270

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 33

ER -