The Invasive Capacity of HPV Transformed Cells Requires the hDlg-Dependent Enhancement of SGEF/RhoG Activity

PLoS Pathogens

Lisa Sharek¹  Rafael Garcia-Mata¹  Vanitha Krishna Subbaiah²  Siaw Shi Boon²  Lawrence Banks²  Paola Massimi²  Michael P. Myers² 

[1] Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America;International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

关键词: Small interfering RNAs;    Immunoprecipitation;    HPV-18;    HeLa cells;    Cytoskeleton;    HPV-16;    Co-immunoprecipitation;    Transfection;   

DOI  :  10.1371/journal.ppat.1002543

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

A major target of the HPV E6 oncoprotein is the human Discs Large (hDlg) tumour suppressor, although how this interaction contributes to HPV-induced malignancy is still unclear. Using a proteomic approach we show that a strong interacting partner of hDlg is the RhoG-specific guanine nucleotide exchange factor SGEF. The interaction between hDlg1 and SGEF involves both PDZ and SH3 domain recognition, and directly contributes to the regulation of SGEF's cellular localization and activity. Consistent with this, hDlg is a strong enhancer of RhoG activity, which occurs in an SGEF-dependent manner. We also show that HPV-18 E6 can interact indirectly with SGEF in a manner that is dependent upon the presence of hDlg and PDZ binding capacity. In HPV transformed cells, E6 maintains a high level of RhoG activity, and this is dependent upon the presence of hDlg and SGEF, which are found in complex with E6. Furthermore, we show that E6, hDlg and SGEF each directly contributes to the invasive capacity of HPV-16 and HPV-18 transformed tumour cells. These studies demonstrate that hDlg has a distinct oncogenic function in the context of HPV induced malignancy, one of the outcomes of which is increased RhoG activity and increased invasive capacity.

【 授权许可】

CC BY