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Molecular and Cellular Biology, October 2007, p. 6647-6658, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00155-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Downregulation of Rap1GAP Contributes to Ras Transformation{triangledown}

Oxana M. Tsygankova,1 Gregory V. Prendergast,1 Kanchan Puttaswamy,2 Yan Wang,2 Michael D. Feldman,3 Hongbin Wang,1 Marcia S. Brose,2,4 and Judy L. Meinkoth1*

Departments of Pharmacology,1 Otorhinolaryngology and Head and Neck Surgery,2 Medicine,4 Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191043

Received 26 January 2007/ Returned for modification 22 March 2007/ Accepted 6 July 2007

Although abundant in well-differentiated rat thyroid cells, Rap1GAP expression was extinguished in a subset of human thyroid tumor-derived cell lines. Intriguingly, Rap1GAP was downregulated selectively in tumor cell lines that had acquired a mesenchymal morphology. Restoring Rap1GAP expression to these cells inhibited cell migration and invasion, effects that were correlated with the inhibition of Rap1 and Rac1 activity. The reexpression of Rap1GAP also inhibited DNA synthesis and anchorage-independent proliferation. Conversely, eliminating Rap1GAP expression in rat thyroid cells induced a transient increase in cell number. Strikingly, Rap1GAP expression was abolished by Ras transformation. The downregulation of Rap1GAP by Ras required the activation of the Raf/MEK/extracellular signal-regulated kinase cascade and was correlated with the induction of mesenchymal morphology and migratory behavior. Remarkably, the acute expression of oncogenic Ras was sufficient to downregulate Rap1GAP expression in rat thyroid cells, identifying Rap1GAP as a novel target of oncogenic Ras. Collectively, these data implicate Rap1GAP as a putative tumor/invasion suppressor in the thyroid. In support of that notion, Rap1GAP was highly expressed in normal human thyroid cells and downregulated in primary thyroid tumors.

* Corresponding author. Mailing address: Department of Pharmacology, University of Pennsylvania School of Medicine, 421 Curie Blvd., 1251 BRB II/III, Philadelphia, PA 19104-6061. Phone: (215) 898-1909. Fax: (215) 573-2236. E-mail: meinkoth{at}pharm.med.upenn.edu

{triangledown} Published ahead of print on 23 July 2007.

Molecular and Cellular Biology, October 2007, p. 6647-6658, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00155-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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