Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer Journal Article


Authors: Kimmelman, A. C.; Hezel, A. F.; Aguirre, A. J.; Zheng, H.; Paik, J. H.; Ying, H.; Chu, G. C.; Zhang, J. X.; Sahin, E.; Yeo, G.; Ponugoti, A.; Nabioullin, R.; Deroo, S.; Yang, S.; Wang, X.; McGrath, J. P.; Protopopova, M.; Ivanova, E.; Zhang, J.; Feng, B.; Tsao, M. S.; Redston, M.; Protopopov, A.; Xiao, Y.; Futreal, P. A.; Hahn, W. C.; Klimstra, D. S.; Chin, L.; DePinho, R. A.
Article Title: Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer
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. © 2008 by The National Academy of Sciences of the USA.
Keywords: signal transduction; cancer survival; controlled study; human tissue; protein expression; unclassified drug; gene mutation; pancreas cancer; pancreatic neoplasms; protein function; protein analysis; phenotype; animals; mice; gene amplification; carcinoma, pancreatic ductal; enzyme activity; protein serine threonine kinase; gene expression regulation, neoplastic; mice, nude; protein-serine-threonine kinases; genomic instability; pancreatic ducts; proto-oncogene proteins c-akt; cell migration; cell movement; cell line, transformed; genomics; pancreas adenocarcinoma; neoplasm invasiveness; pancreatic cancer; cell invasion; cell motility; rho gtp-binding proteins; rac protein; rho kinase; p21-activated kinases; guanosine triphosphatase; p21 activated kinase 4; rac; pak4; rio kinase3; protein riok3
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 105
Issue: 49
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2008-12-09
Start Page: 19372
End Page: 19377
Language: English
DOI: 10.1073/pnas.0809966105
PUBMED: 19050074
PROVIDER: scopus
PMCID: PMC2614768
DOI/URL:
Notes: --- - "Cited By (since 1996): 26" - "Export Date: 17 November 2011" - "CODEN: PNASA" - "Source: Scopus"
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  1. David S Klimstra
    978 Klimstra