The invasive capacity of HPV transformed cells requires the hDlg-dependent enhancement of SGEF/RhoG activity

PLoS Pathog. 2012 Feb;8(2):e1002543. doi: 10.1371/journal.ppat.1002543. Epub 2012 Feb 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Alphapapillomavirus / genetics*
  • Alphapapillomavirus / physiology
  • Animals
  • Cell Adhesion / genetics
  • Cell Movement / genetics*
  • Cell Movement / physiology
  • Cell Transformation, Viral / genetics
  • Cell Transformation, Viral / physiology*
  • Cells, Cultured
  • Guanine Nucleotide Exchange Factors / chemistry
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Guanine Nucleotide Exchange Factors / physiology
  • HEK293 Cells
  • HeLa Cells
  • Human papillomavirus 16 / genetics
  • Human papillomavirus 16 / physiology
  • Human papillomavirus 18 / genetics
  • Human papillomavirus 18 / physiology
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mice
  • Protein Structure, Tertiary / physiology
  • Up-Regulation / genetics
  • rho GTP-Binding Proteins / chemistry
  • rho GTP-Binding Proteins / metabolism*
  • rho GTP-Binding Proteins / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • DLG1 protein, human
  • Guanine Nucleotide Exchange Factors
  • Membrane Proteins
  • SGEF protein, human
  • RHOG protein, human
  • rho GTP-Binding Proteins