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Assia Shisheva, Ph.D.
Professor of Physiology
Associate Faculty, CMMG
4237 Scott Hall
540 E. Canfield
Detroit, MI 48201
(313) 577-5674




Dr. Shisheva joined Wayne State University in 1996 with the ambition to discover new molecular players in her life-long field of scientific interest – the mechanism of insulin-regulated glucose transport. Immediately upon setting her lab, she embarked on a risky expedition searching for genes selectively expressed in adipose and fat tissue. This effort paid off by the isolation of an exceedingly large evolutionarily-conserved enzyme. Dr. Shisheva called it PIKfyve (for PhosphoInositide Kinase for position five containing a fyve finger domain), based on the subsequent characterization of its kinase activity towards phosphoinositides and other features. PIKfyve and its products were found to function as positive regulators of insulin responsiveness. Since then, the multifaceted role of PIKfyve and its associated proteins in phosphoinositide metabolism and cellular functions has become the major focus of Dr. Shisheva’s research.

PIKfyve is an essential component of the mammalian cell endocytic machinery that binds to membrane phosphatidyl inositol (PI) 3P (3-phosphate) and synthesizes PI3,5P2 and PI5P. PIKfyve mutants defective in PI3,5P2 synthesis or PIKfyve protein ablation cause enormous cytoplasmic vacuoles. More recent studies reveal that PIKfyve delivers its action in a complex with two other protein partners: ArPIKfyve and Sac3. ArPIKfyve activates PIKfyve lipid kinase activity whereas Sac3 is a lipid phosphatase using PI3,5P2 as a substrate. Thus PIKfyve appears to be a part of a molecular machine synthesizing and turning over PI3,5P2, thereby regulating endosomal traffic. 
Dr. Shisheva’s findings have attracted a lot of scientific interest. In addition to confirming her observations at cellular level, work by others has established that PIKfyve and Sac3 mutations are associated with human genetic disorders (Francois-Neetens Mouchetee fleck corneal dystrophy and Charcot-Marie-Tooth neuropathy, respectively). In multicellular model organisms knockout of PIKfyve is lethal, whereas mouse knockouts of ArPIKfyve and Sac3 result in similar neurodegeneration and early postnatal death. Finally, PIKfyve ablation inhibits HIV propagation, further supporting its essential role in endocytic functions. You could read Dr. Shisheva’s most recent reviews on the functionality of PIKfyve and associated proteins here and here.
These observations underscore the importance of fundamental advances in the field and the expectaitons that further studies may provide targets for diagnosis and treatment of human disease.
Dr. Shisheva's research is supported by NIH and ADA. 

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A list of Dr. Shisheva's peer reviewed publications and review articles can be found at PubMed-Shisheva



Shisheva, A., C. DeMarco, O. Ikonomov, D. Sbrissa, PIKfyve and the acute insulin actions.  In: A. Sima and E. Shafrir (eds.), Insulin Signaling: From Cultured Cells to Animal Models pp. 189-210, 2002 bullet LAB PERSONNEL (past and present) bullet Graduate Students bullet

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    (Please click on the thumbnails below for an expanded view)

The seven P!s and their metabolism.


Schematic diagram of the domain structure of the evolutionary conserved mammalian and yeast counterparts engaged in PtdIns(3,5)P2 metabolism.

General scheme of the endocytosis and proposed model for the locus and mode of action of PIKfyve and its physically associated partners.

Schematic model for the sites of PI's action in insulin-regulated multi-step process of GLUT4 translocation in adipose and muscle cells.

Model for Ptdlns(3)P-Ptdlns(3,5)P2 Interconversion

PIKfyve Pleiotropic Cell Function
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                                                   Update: 09/02/2014 by CRC.