Kimmelman, A. C., Hezel, A. F., Aguirre, A. J., Zheng, H. W., Paik, J. H., Ying, H. Q., Chu, G. C., Zhang, J. X., Sahin, E., Yeo, G. M., Ponugoti, A., Nabioullin, R., Deroo, S., Yang, S. D., Wang, X. X., McGrath, J. P., Protopopova, M., Ivanova, E., Zhang, J. H., Feng, B., Tsao, M. S., Redston, M., Protopopov, A., Xiao, Y. H., Futreal, P. A., Hahn, W. C., Klimstra, D. S., Chin, L., DePinho, R. A. (December 2008) Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proceedings of the National Academy of Sciences of the United States of America, 105 (49). pp. 19372-19377. ISSN 0027-8424
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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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Pak4 pancreatic cancer Rac Rio Kinase3 NUCLEOTIDE POLYMORPHISM ARRAYS ANCHORAGE-INDEPENDENT GROWTH CELL-CYCLE PROGRESSION PROTEIN-KINASE HOMOZYGOUS DELETIONS SACCHAROMYCES-CEREVISIAE HYBRIDIZATION REVEALS RIO KINASES PAK4 ADENOCARCINOMA Multidisciplinary Sciences |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > GTPase bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > G protein > Rho diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Zheng lab |
| Depositing User: | Matt Covey |
| Date: | December 2008 |
| Date Deposited: | 22 Aug 2014 19:35 |
| Last Modified: | 22 Aug 2014 19:35 |
| PMCID: | PMC2614768 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30706 |
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