Gab1 is essential for membrane translocation, activity and integrity of mTORCs after EGF stimulation in urothelial cell carcinoma

Oncotarget. 2015 Jan 30;6(3):1478-89. doi: 10.18632/oncotarget.2756.

Abstract

Urothelial carcinoma is the most common type of malignancy in long-term dialysis patients and kidney transplant recipients in Taiwan. mTORCs (mammalian target of rapamycin complexes) and EGF are important in urothelial carcinoma. To identify the regulation of mTORCs upon EGF stimulation is necessary. mTOR integrates signals from growth factors via mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). The mechanism of mTORC1 action has been widely studied; however, the regulation of mTORC2 has not been well studied. Here, we demonstrate that Gab1 is an important upstream regulator in EGF-mediated activation of mTORCs. In our study, we confirm that mTORCs translocate from the cytoplasm to the plasma membrane via the PH domain of Gab1 upon EGF stimulation. Moreover, Gab1 associates with mTORCs. This association stabilizes the integrity of mTORCs and induces mTORC activity. Compared to normal bladder tissue, the expression of Gab1 and activity of mTORCs are elevated in urothelial carcinoma. Collectively, our results suggest that Gab1 is an essential regulator of the EGF-mediated mTORC pathways and may potentially be used as a biomarker for urothelial carcinoma to predict diagnosis and drug response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line, Tumor
  • Epidermal Growth Factor / pharmacology*
  • Female
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Rats
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Transfection
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism*
  • Urinary Bladder Neoplasms / pathology

Substances

  • Adaptor Proteins, Signal Transducing
  • GAB1 protein, human
  • Gab1 protein, rat
  • Multiprotein Complexes
  • Phosphoproteins
  • Epidermal Growth Factor
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • TOR Serine-Threonine Kinases