UBTOR/KIAA1024 regulates neurite outgrowth and neoplasia through mTOR signaling

The mTOR signaling pathways regulate cell growth and are involved in multiple human diseases. Here, we identify UBTOR, a previously unannotated gene as a functional player in regulating cell growth and mTOR signaling. Reduction of UBTOR function in cultured hippocampal neurons and PC12 cells promotes neurite outgrowth. UBTOR depletion activates mTOR signaling and promotes cell growth, whilst UBTOR overexpression suppresses colony formation in cancer cell lines. Studies in cultured cells and zebrafish model show that UBTOR inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR, and ubtor gene disruption result in higher mTOR activity and aggravate HRAS(G12V) induced neoplasia in the zebrafish. Lastly, UBTOR depletion promotes tumor growth and mTOR signaling in a xenograft mouse model. Together, our results demonstrate how UBTOR regulates cell growth and neoplasia via mTOR signaling.Author summary: Cell growth is a fundamental aspect of cell behavior in all organisms. The mTOR signaling pathways are essential for cell growth and clinically mis-regulation of the mTOR pathways are implicated in human diseases including tumor formation, obesity, epilepsy, autism and neurodegeneration. Here, we identify a novel gene, Ubtor as a functional player in regulating cell growth and mTOR signaling. Inhibiting Ubtor function promotes cell growth in neurons and cancer cells. Increasing Ubtor function reduces cancer cell growth. Functional analyses in human cells and the zebrafish model indicate Ubtor inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR, and ubtor gene disruption resulted in higher mTOR activity and aggravated cancer formation in the zebrafish. UBTOR depletion promotes tumor growth and mTOR signaling in xenograft-bearing mice. Thus our study provide evidence that Ubtor constitutes a novel negative feedback mechanism to control mTOR signaling and cell growth, and manipulations of Ubtor function may potentially be utilized to optimize mTOR signaling activities for treatments of cancers and other diseases.