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Journal of Virology, January 2003, p. 1614-1620, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1614-1620.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The High-Risk Human Papillomavirus Type 16 E6 Counters the GAP Function of E6TP1 toward Small Rap G Proteins

Latika Singh,1 Qingshen Gao,1 Ajay Kumar,1 Takaya Gotoh,2 David E. Wazer,1 Hamid Band,3 Larry A. Feig,2 and Vimla Band1,2*

Division of Radiation and Cancer Biology, Department of Radiation Oncology, New England Medical Center,1 Department of Biochemistry, Tufts University School of Medicine,2 Division of Rheumatology, Immunology and Allergy, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts3

Received 2 July 2002/ Accepted 14 October 2002

We have recently identified E6TP1 (E6-targeted protein 1) as a novel high-risk human papillomavirus type 16 (HPV16) E6-binding protein. Importantly, mutational analysis of E6 revealed a strong correlation between the transforming activity and its abilities to bind and target E6TP1 for ubiquitin-mediated degradation. As a region within E6TP1 has high homology with GAP domains of known and putative Rap GTPase-activating proteins (GAPs), these results raised the possibility that HPV E6 may alter the Rap small-G-protein signaling pathway. Using two different approaches, we now demonstrate that human E6TP1 exhibits GAP activity for Rap1 and Rap2, confirming recent findings that a closely related rat homologue exhibits Rap-specific GAP activity. Using mutational analysis, we localize the GAP activity to residues 240 to 945 of E6TP1. Significantly, we demonstrate that coexpression of HPV16 E6, by promoting the degradation of E6TP1, enhances the GTP loading of Rap. These results support a role of Rap small-G-protein pathway in E6-mediated oncogenesis.

* Corresponding author. Mailing address: Department of Radiation Oncology, Box 824, New England Medical Center, 750 Washington St., Boston, MA 02111. Phone: (617) 636-4776. Fax (617) 636-6205. E-mail: VBAND{at}lifespan.org.

Journal of Virology, January 2003, p. 1614-1620, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1614-1620.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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