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Tuberous sclerosis complex (TSC) is caused by inactivating mutations in either TSC1 or TSC2 and is characterized by uncontrolled mTORC1 activation. Drugs that reduce mTOR activity are only partially successful in the treatment of TSC, suggesting that mTOR-independent pathways play a role in disease development. Here, kinome profiles of wild-type and Tsc2(-/-) mouse embryonic fibroblasts (MEFs) were generated, revealing a prominent role for PAK2 in signal transduction downstream of TSC1/2. Further investigation showed that the effect of the TSC1/2 complex on PAK2 is mediated through RHEB, but is independent of mTOR and p21RAC. We also demonstrated that PAK2 over-activation is likely responsible for the migratory and cell cycle abnormalities observed in Tsc2(-/-) MEFs. Finally, we detected high levels of PAK2 activation in giant cells in the brains of TSC patients. These results show that PAK2 is a direct effector of TSC1-TSC2-RHEB signaling and a new target for rational drug therapy in TSC.
Pubmed ID: 26412398 RIS Download
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Welcome to Michael Eisens lab in the Howard Hughes Medical Institute (HHMI) at University of California at Berkeley (UCB) and the Lawrence Berkeley National Lab (LBNL). We are part of the Department of Molecular and Cell Biology of UCB and the Genomics Division of LBNL, and the. We are located in Stanley Hall on the Berkeley campus.Our lab applies computational and experimental genomic approaches to study how genome sequences specify organismal form and function. We are particularly interested in the regulation of gene expression, and focus on how the information that specifies when and where genes are expressed is encoded in genome sequences, the role that regulated gene expression plays in animal development and the response of microbes to their environments, and how variation in and evolution of gene expression contributes to phenotypic variation and the remarkable diversity of life on Earth. This site contains a more detailed description of our research projects, an introduction to members of the lab, reprints of all of our publications, free downloadable and web-based software. Sponsor. Experimental work described here was supported by a Howard Hughes Medical Institute Investigator award to MBE and by National Institutes of Health (NIH) grant GM704403 to MBE and MDB. Computational analyses were supported in by NIH grant HG002779 to MBE. Work at Lawrence Berkeley National Laboratory was conducted under Department of Energy contract DE-AC02-05CH11231. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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