Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1

van der Horst, E. H., Degenhardt, Y. Y., Strelow, A., Slavin, A., Chinn, L., Orf, J., Rong, M., Li, S., See, L. H., Nguyen, K. Q., Hoey, T., Wesche, H., Powers, S. (November 2005) Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1. Proceedings of the National Academy of Sciences of the United States of America, 102 (44). pp. 15901-6. ISSN 0027-8424

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URL: http://www.ncbi.nlm.nih.gov/pubmed/16247015
DOI: 10.1073/pnas.0508014102

Abstract

Metastasis of primary tumors leads to a very poor prognosis for patients suffering from cancer. Although it is well established that not every tumor will eventually metastasize, it is less clear whether primary tumors acquire genetic alterations in a stochastic process at a late stage, which make them invasive, or whether genetic alterations acquired early in the process of tumor development drive primary tumor growth and determine whether this tumor is going to be metastatic. To address this issue, we tested genes identified in a large-scale comparative genomic hybridization analysis of primary tumor for their ability to confer metastatic properties on a cancer cell. We identified amplification of the ACK1 gene in primary tumors, which correlates with poor prognosis. We further show that overexpression of Ack1 in cancer cell lines can increase the invasive phenotype of these cells both in vitro and in vivo and leads to increased mortality in a mouse model of metastasis. Biochemical studies show that Ack1 is involved in extracellular matrix-induced integrin signaling, ultimately activating signaling processes like the activation of the small GTPase Rac. Taken together, this study supports a theory from Bernards and Weinberg [Bernards, R. & Weinberg, R. A. (2002) Nature 418, 823], which postulates that the tendency to metastasize is largely predetermined.

Item Type: Paper
Uncontrolled Keywords: Animals Cell Line, Tumor Crk-Associated Substrate Protein/metabolism *Gene Amplification Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Integrin alpha3beta1/metabolism Lung Neoplasms/secondary Mice Neoplasm Metastasis/*genetics Neoplasm Transplantation Prognosis Protein-Tyrosine Kinases/*genetics/metabolism/*physiology Signal Transduction Transplantation, Heterologous Tumor Cells, Cultured rac GTP-Binding Proteins/metabolism
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene amplification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
diseases & disorders > cancer > metastasis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Powers lab
Depositing User: Matt Covey
Date: 1 November 2005
Date Deposited: 25 Feb 2014 17:48
Last Modified: 11 Jan 2018 16:53
PMCID: PMC1276100
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29535

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