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

// Chi-Hao Chang 1 , Po-Chao Chan 2 , Jian-Ri Li 3 , Chun-Jung Chen 4, 5 , Jeng-Jer Shieh 4, 5 , Yun-Ching Fu 6 , Hong-Chen Chen 2, 5 , Ming-Ju Wu 1, 5, 7, 8, 9 1 Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan 2 Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan 3 Department of Surgery, Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan 4 Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan 5 Institute of Biomedical Science, National Chung Hsing University, Taichung, Taiwan 6 Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan 7 Department of Medicine, Division of Nephrology, Taichung Veterans General Hospital, Taichung, Taiwan 8 School of Medicine, Chung Shan Medical University, Taichung, Taiwan 9 Graduate Institute of Clinical Medical Science, School of Medicine, China Medical University, Taichung, Taiwan Correspondence to: Ming-Ju Wu, e-mail: wmj530@gmail.com Hong-Chen Chen, e-mail: hcchen@nchu.edu.tw Keywords: mTORCs, Gab1, EGF, urothelial carcinoma Received: October 12, 2014      Accepted: November 16, 2014      Published: January 20, 2015 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.