What is the Physiological Role of PI(3,5)P2?

Project Summary

The phosphatidylinositide lipid PI(3,5)P2 is synthesized by an enzyme named Pikfyve or Fab1 in eukaryotes. This enzyme is regulated by at least three conserved adaptor proteins, Vac14, Fig4 and Atg18. Having only been recently uncovered, the role of this enzyme and its lipid products is still under investigation.

Recently we have observed that this lipid is synthesized in response to increased nutrient levels in mammalian cells. We also described a loss of mTORC1 function associated with decreases in PI(3,5)P2 levels. In collaboration with several investigators at the University of Michigan we have put forth the hypothesis that direct binding of the Raptor WD40 domain to PI(3,5)P2 is important for lipid regulation of this complex as far back as in budding yeast. Using newly generated genetic tools, we are examining the role of Pikfyve and its regulatory proteins in mice and yeast, focusing on the newly established role of this lipid in nutrient sensing.

Who is Working on This?

Dave Bridges
Assistant Professor, Department of Nutritional Sciences, University of Michigan since 2016-06-01


What have we published on this topic?

Natsuko JIn, Kai Mao, Yui Jin, Gela Tevadze, Emily Kauffman, Sujin Park, Dave Bridges, Robbie Loewith, Alan Saltiel, Daniel Klionsky and Lois Weisman. Roles for PI(3,5)P2 in nutrient sensing through TORC1 2014. Molecular Biology of the Cell 25(7):1171-85 Full Text Details.
Sergey Zolov, Dave Bridges, Yanling Zhang, Wei-Wei Li, Ellen Riehle, Rakesh Verma, Guy Lenk, Kimber Converso-Baran, Thomas Weide, Roger Albin, Alan Saltiel, Miriam Meisler, Mark Russell and Lois Weisman. In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P. 2012. Proceedings of the National Academy of Sciences of the United States of America 109(43):17472-7 Full Text Details.
Dave Bridges and Alan Saltiel. Phosphoinositides in insulin action and diabetes. 2012. Current topics in microbiology and immunology 362:61-85 Full Text Details.
Dave Bridges, Kaleigh Fisher, Sergey Zolov, Tingting Xiong, Ken Inoki, Lois Weisman and Alan Saltiel. Rab5 proteins regulate activation and localization of target of rapamycin complex 1. 2012. The Journal of biological chemistry 287(25):20913-21 Full Text Details.
Dave Bridges, Jing-Tyan Ma, Sujin Park, Ken Inoki, Lois Weisman and Alan Saltiel. Phosphatidylinositol 3,5-bisphosphate plays a role in the activation and subcellular localization of mechanistic target of rapamycin 1. 2012. Molecular biology of the cell 23(15):2955-62 Full Text Details.
Irfan Lodhi, Dave Bridges, Shian-Huey Chiang, Yanling Zhang, Alan Cheng, Lynn Geletka, Lois Weisman and Alan Saltiel. Insulin stimulates phosphatidylinositol 3-phosphate production via the activation of Rab5. 2008. Molecular biology of the cell 19(7):2718-28 Full Text Details.

What are some key papers on this topic?

Ognian Ikonomov, Diego Sbrissa, Khortnal Delvecchio, Han-Zhong Feng, Gregory Cartee, Jian-Ping Li and Assia Shisheva. Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type swit 2013. American journal of physiology. Endocrinology and metabolism 305(1):E119-31 Full Text Details.
Shunsuke Takasuga, Yasuo Horie, Junko Sasaki, Ge-Hong Sun-Wada, Nobuyuki Kawamura, Ryota Iizuka, Katsunori Mizuno, Satoshi Eguchi, Satoshi Kofuji, Hirotaka Kimura, Masakazu Yamazaki, Chihoko Horie, Eri Odanaga, Yoshiko Sato, Shinsuke Chida, Kenji Kontani, Akihiro Harada, Akihiro Katada, Akira Suzuki, Yoh Wada, Hirohide Ohnishi and Takehiko Sasaki. Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine. 2013. Proceedings of the National Academy of Sciences of the United States of America 110(5):1726-31 Full Text Our Thoughts Details.


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