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DAP1 as a Novel Substrate of MOTR
Yeda R&D Co. Ltd Israel flag Israel
Abstract ID: 1697
Autophagy is primarily a protective process for the cell, but it can also play a role in cell death. For example, autophagy is vital for embryonic developments, and...
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Introduction/Background

Autophagy is primarily a protective process for the cell, but it can also play a role in cell death. For example, autophagy is vital for embryonic developments, and can prevent cancer cells from spreading while deregulated autophagy was suggested to play a role in autism. Although autophagy is highly regulated, controlled by both positive and negative regulators little is known about the mechanisms that govern balanced autophagy in health.

Aims/Hypothesis

Consequently, there is no targeted pharmacological solution for diseases that are attributed to dysregulation in autophagy.

Results

In this technology, a way of modulating autophagy is introduced, via the newly identified death-associated protein 1 (DAP1) which serves as autophagy suppressor. DAP1 is a direct substrate of the mammalian target of rapamycin (mTOR). mTOR serves as the cells' integrator by combining inputs from upstream pathways thus it plays a key role in the life of the cell and affects many fundamental cellular functions. This discovery opens a new window of treating autophagy related diseases.

This technology presents DAP1, a novel substrate of mTOR that negatively regulates autophagy. Initially, a link of DAP1 to autophagy was apparent in that its knockdown enhanced autophagy flux. Also, it displayed a rapid decline in its phosphorylation in response to amino acid starvation. Next, by mapping the phosphorylation sites and analyzing phosphorylation mutants it has been demonstrated that DAP1 is functionally silenced in growing cells via mTOR-dependent phosphorylation on Ser3 and Ser51. Last, Inactivation of mTOR during starvation caused a rapid reduction in these phosphorylation sites and converted the protein into an active suppressor of autophagy.

Conclusion

We have elucidated a target for drug design to treat a diverse set of diseases such as neurodegenerative diseases, cancer, and cellular aging.

Relevance/Opportunity

Please enquire regarding licensing or codevelopment partnerships quoting reference no. 1697.
FEATURED
Last Updated May 2015
Technology Type MECHANISM
Phase of Development PRECLINICAL
CORPORATION