Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer
Open Access
- 9 December 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 105 (49), 19372-19377
- https://doi.org/10.1073/pnas.0809966105
Abstract
Pancreas ductal adenocarcinoma (PDAC) is a highly lethal cancer that typically presents as advanced, unresectable disease. This invasive tendency, coupled with intrinsic resistance to standard therapies and genome instability, are major contributors to poor long-term survival. The genetic elements governing the invasive propensity of PDAC have not been well elucidated. Here, in the course of validating resident genes in highly recurrent and focal amplifications in PDAC, we have identified Rio Kinase 3 (RIOK3) as an amplified gene that alters cytoskeletal architecture as well as promotes pancreatic ductal cell migration and invasion. We determined that RIOK3 promotes its invasive activities through activation of the small G protein, Rac. This genomic and functional link to Rac signaling prompted a genome wide survey of other components of the Rho family network, revealing p21 Activated Kinase 4 (PAK4) as another amplified gene in PDAC tumors and cell lines. Like RIOK3, PAK4 promotes pancreas ductal cell motility and invasion. Together, the genomic and functional profiles establish the Rho family GTP-binding proteins as integral to the hallmark invasive nature of this lethal disease.Keywords
This publication has 42 references indexed in Scilit:
- The Pak4 Protein Kinase Plays a Key Role in Cell Survival and Tumorigenesis in Athymic MiceMolecular Cancer Research, 2008
- Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary CancerPLoS Genetics, 2008
- Common and Distinct Genomic Events in Sporadic Colorectal Cancer and Diverse Cancer TypesCancer Research, 2007
- Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arraysOncogene, 2007
- Identification of Protein Networks Associated with the PAK1−βPIX−GIT1−Paxillin Signaling Complex by Mass SpectrometryJournal of Proteome Research, 2006
- Identifying Allelic Loss and Homozygous Deletions in Pancreatic Cancer without Matched Normals Using High-Density Single-Nucleotide Polymorphism ArraysCancer Research, 2006
- Structure and activity of the atypical serine kinase Rio1The FEBS Journal, 2005
- Late Cytoplasmic Maturation of the Small Ribosomal Subunit Requires RIO Proteins in Saccharomyces cerevisiaeMolecular and Cellular Biology, 2003
- Requirement for PAK4 in the Anchorage-independent Growth of Human Cancer Cell LinesJournal of Biological Chemistry, 2002
- Comparative Phenotypic Studies of Duct Epithelial Cell Lines Derived from Normal Human Pancreas and Pancreatic CarcinomaThe American Journal of Pathology, 1998