'An Impact of GTP-Metabolism on Cancers and Metabolic Diseases'

Speaker: Atsuo T. Sasaki, Ph.D.
Univ Cincinnati Cancer Institute
http://www.thesasakilab.org

Title: An Impact of GTP-Metabolism on Cancers and Metabolic Diseases

Abstract: Detection of the intracellular concentration of energy molecules is critical for cell proliferation and survival. Key enzymes that translate changes in ATP energy levels into signal transduction are AMPK and mTOR. Besides ATP, cells utilize GTP as a dynamic energy molecule for specific cellular processes, such as cytoskeletal reorganization, intracellular trafficking, signal transduction, and protein synthesis. Rapidly growing cells, such as cancer cells, have elevated GTP levels, while ATP levels not. However the molecular mechanisms by which cells detect GTP levels are not fully understood.

In stark contrast with empirical rule of ATP utilization by kinases, we discovered a novel type of signaling kinase (tentatively named SSK1: Super Signaling Kinase-1) that utilizes GTP as a phospho-donor. The co-crystal structure of SSK1 and a guanine nucleotide complex reveals that a unique hydrophobic grove enables guanine nucleotide sliding. In addition, a unique pit in the nucleotide binding site induces “Tetris spin” of guanine nucleotide to fit into the pocket, engaging GTP for high affinity binding. Importantly, our data suggest that SSK1 activity is regulated by cellular GTP-level and in return SSK1 regulates growth signaling and cell metabolism. In the meeting, I will discuss the role of SSK1 as a potential sensor for GTP-metabolism and its impact on cancers and metabolic diseases.

Host: Tadashi Yamamoto, Cell Signal Unit