title: Gab1 is essential for membrane translocation, activity and integrity of mTORCs after EGF stimulation in urothelial cell carcinoma.
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.
authors.affiliation: Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan.
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Po-Chao
authors.initials: PC
authors.lastname: Chan
authors.affiliation: Department of Surgery, Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Jian-Ri
authors.initials: JR
authors.lastname: Li
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.|Institute of Biomedical Science, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Chen
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.|Institute of Biomedical Science, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Jeng-Jer
authors.initials: JJ
authors.lastname: Shieh
authors.affiliation: Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Fu
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.|Institute of Biomedical Science, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Hong-Chen
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan.|Institute of Biomedical Science, National Chung Hsing University, Taichung, Taiwan.|Department of Medicine, Division of Nephrology, Taichung Veterans General Hospital, Taichung, Taiwan.|School of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Graduate Institute of Clinical Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Ming-Ju
authors.initials: MJ
authors.lastname: Wu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; C490896:Gab1 protein, rat; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D004815:Epidermal Growth Factor; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases