title: Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity.
abstract: RNA polymerase I-mediated rRNA production is a key determinant of cell growth. Despite extensive studies, the signaling pathways that control RNA polymerase I-mediated rRNA production are not well understood. Here we provide original evidence showing that RNA polymerase I transcriptional activity is tightly controlled by integrin signaling. Furthermore, we show that a signaling axis consisting of focal adhesion kinase (FAK), Src, phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR mediates the effect of integrin signaling on rRNA transcription. Additionally, we show that in kindlin-2 knockout mouse embryonic fibroblasts, overactivation of Ras, Akt, and Src can successfully rescue the defective RNA polymerase I activity induced by the loss of kindlin-2. Finally, through experiments with inhibitors of FAK, Src, and PI3K and rescue experiments in MEFs, we found that the FAK/Src/PI3K/Akt signaling pathway to control rRNA transcription is linear. Collectively, these studies reveal, for the first time, a pivotal role of integrin signaling in regulation of RNA polymerase I transcriptional activity and shed light on the downstream signaling axis that participates in regulation of this key aspect of cell growth.
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen, China Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology, Shenzhen, China Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA wucy@sustc.edu.cn zhangyd@sustc.edu.cn.
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen, China.
authors.forename: Jin
authors.initials: J
authors.lastname: You
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen, China.
authors.forename: Jijun
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen, China.
authors.forename: Xingshun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen, China wucy@sustc.edu.cn zhangyd@sustc.edu.cn.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012318:RNA Polymerase I / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016023:Integrins; D012335:RNA, Ribosomal; C546843:mTOR protein, mouse; D058539:Phosphatidylinositol 3-Kinase; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D012318:RNA Polymerase I