Rac1 Activation Driven by 14-3-3f Dimerization Promotes Prostate Cancer Cell-Matrix Interactions, Motility and Transendothelial Migration

Hdl Handle:
http://hdl.handle.net/10675.2/807
Title:
Rac1 Activation Driven by 14-3-3f Dimerization Promotes Prostate Cancer Cell-Matrix Interactions, Motility and Transendothelial Migration
Authors:
Goc, Anna; Abdalla, Maha; Al-Azayzih, Ahmad; Somanath, Payaningal R.
Abstract:
14-3-3 proteins are ubiquitously expressed dimeric adaptor proteins that have emerged as key mediators of many cell signaling pathways in multiple cell types. Its effects are mainly mediated by binding to selective phosphoserine/threonine proteins. The importance of 14-3-3 proteins in cancer have only started to become apparent and its exact role in cancer progression as well as the mechanisms by which 14-3-3 proteins mediate cancer cell function remain unknown. While protein 14-3-3s is widely accepted as a tumor suppressor, 14-3-3f, b and c isoforms have been shown to have tumor promoting effects. Despite the importance of 14-3-3 family in mediating various cell processes, the exact role and mechanism of 14-3-3f remain unexplored. In the current study, we investigated the role of protein 14-3-3f in prostate cancer cell motility and transendothelial migration using biochemical, molecular biology and electric cell-substrate impedance sensing approaches as well as cell based functional assays. Our study indicated that expression with wild-type protein 14-3-3f significantly enhanced Rac activity in PC3 cells. In contrast, expression of dimer-resistant mutant of protein 14-3-3f (DM-14-3-3) inhibited Rac activity and associated phosphorylation of p21 activated kinase-1 and 2. Expression with wild-type 14-3-3f or constitutively active Rac1 enhanced extracellular matrix recognition, lamellipodia formation, cell migration and trans-endothelial migration by PC3 cells. In contrast, expression with DM 14-3-3f or DN-Rac1 in PC3 cells significantly inhibited these cell functions. Our results demonstrate for the first time that 14-3-3f enhances prostate cancer cell-matrix interactions, motility and transendothelial migration in vitro via activation of Rac1-GTPase and is an important target for therapeutic interventions for prostate cancer.
Citation:
PLoS One. 2012 Jul 13; 7(7):e40594
Issue Date:
13-Jul-2012
URI:
http://hdl.handle.net/10675.2/807
DOI:
10.1371/journal.pone.0040594
PubMed ID:
22808202
PubMed Central ID:
PMC3396618
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Medicine Faculty: Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorGoc, Annaen_US
dc.contributor.authorAbdalla, Mahaen_US
dc.contributor.authorAl-Azayzih, Ahmaden_US
dc.contributor.authorSomanath, Payaningal R.en_US
dc.date.accessioned2012-10-26T20:30:47Z-
dc.date.available2012-10-26T20:30:47Z-
dc.date.issued2012-07-13en_US
dc.identifier.citationPLoS One. 2012 Jul 13; 7(7):e40594en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22808202en_US
dc.identifier.doi10.1371/journal.pone.0040594en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/807-
dc.description.abstract14-3-3 proteins are ubiquitously expressed dimeric adaptor proteins that have emerged as key mediators of many cell signaling pathways in multiple cell types. Its effects are mainly mediated by binding to selective phosphoserine/threonine proteins. The importance of 14-3-3 proteins in cancer have only started to become apparent and its exact role in cancer progression as well as the mechanisms by which 14-3-3 proteins mediate cancer cell function remain unknown. While protein 14-3-3s is widely accepted as a tumor suppressor, 14-3-3f, b and c isoforms have been shown to have tumor promoting effects. Despite the importance of 14-3-3 family in mediating various cell processes, the exact role and mechanism of 14-3-3f remain unexplored. In the current study, we investigated the role of protein 14-3-3f in prostate cancer cell motility and transendothelial migration using biochemical, molecular biology and electric cell-substrate impedance sensing approaches as well as cell based functional assays. Our study indicated that expression with wild-type protein 14-3-3f significantly enhanced Rac activity in PC3 cells. In contrast, expression of dimer-resistant mutant of protein 14-3-3f (DM-14-3-3) inhibited Rac activity and associated phosphorylation of p21 activated kinase-1 and 2. Expression with wild-type 14-3-3f or constitutively active Rac1 enhanced extracellular matrix recognition, lamellipodia formation, cell migration and trans-endothelial migration by PC3 cells. In contrast, expression with DM 14-3-3f or DN-Rac1 in PC3 cells significantly inhibited these cell functions. Our results demonstrate for the first time that 14-3-3f enhances prostate cancer cell-matrix interactions, motility and transendothelial migration in vitro via activation of Rac1-GTPase and is an important target for therapeutic interventions for prostate cancer.en_US
dc.rightsGoc et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectDevelopmental Biologyen_US
dc.subjectMorphogenesisen_US
dc.subjectCell Migrationen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectSignal Transductionen_US
dc.subjectSignaling in Cellular Processesen_US
dc.subjectGTPase signalingen_US
dc.subjectCell Adhesionen_US
dc.subjectExtracellular Matrixen_US
dc.subjectMedicineen_US
dc.subjectOncologyen_US
dc.subjectBasic Cancer Researchen_US
dc.subjectCancer Detection and Diagnosisen_US
dc.subjectCancer Preventionen_US
dc.subjectCancer Treatmenten_US
dc.titleRac1 Activation Driven by 14-3-3f Dimerization Promotes Prostate Cancer Cell-Matrix Interactions, Motility and Transendothelial Migrationen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3396618en_US
dc.contributor.corporatenameDepartment of Medicine-
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