Interview with Dr. Ayyadevara & Dr. Shmookler Reis from the Central Arkansas Veterans Healthcare Service and the University of Arkansas

Oncotarget published " PIP3-binding proteins promote age-dependent protein aggregation and limit survival in C. elegans " which reported that Class-I phosphatidylinositol 3-kinase converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate.

Proteins with domains that specifically bind that head-group are thus tethered to the inner plasma-membrane surface where they have an enhanced likelihood of interaction with other PIP3-bound proteins, in particular other components of their signaling pathways.

Null alleles of the C. elegans age-1 gene, encoding the catalytic subunit of PI3KI, lack any detectable class-I PI3K activity and so cannot form PIP3. These mutant worms survive almost 10-fold longer than the longest-lived normal control, and are highly resistant to a variety of stresses including oxidative and electrophilic challenges.

The authors used ligand-affinity capture to identify membrane-bound proteins downstream of PI3KI that preferentially bind PIP3. Computer modeling supports a subset of candidate proteins predicted to directly bind PIP3 in preference to PIP2, and functional testing by RNAi knockdown confirmed candidates that partially mediate the stress-survival, aggregation-reducing and longevity benefits of PI3KI disruption.

In this Oncotarget study, PIP3-specific candidate sets are highly enriched for proteins previously reported to affect translation, stress responses, lifespan, proteostasis, and lipid transport.

However, very few proteins in these families have been shown to preferentially bind PIP3, and protein homology has proven insufficient to identify PIP3-specific binding.

We used PIP3- and PIP2-affinity enrichment to compare proteins from isogenic strains that differ genetically in their ability to make PIP3, coupled to proteomic identification of the binding proteins.

Molecular modeling of proteins that show preferential binding to PIP3 over PIP2 allows us to extend structural prediction beyond PH-domain proteins, with the potential for confirmation by functional testing.

Proteins with reported specificity for PIP3 include the serine/threonine kinases AKT and PDK-1; Phospholipase C isoforms; atypical protein kinase C, aPKC; cytohesins; general receptor for phosphoinositides 1, GRP1; kindlin3; IL-2 inducible T-cell kinase, ITK; Skap-hom; and Arf GTPase-activating protein 1.

Protein domains reported to confer PIP3-specific binding in some proteins include pleckstrin homology domains, Phox-homology and FYVE domains, P2X domains, and the SYLF domain

The Shmookler Reis/Ayyadevara Research team concluded in their Oncotarget Priority Research Paper that In view of the importance of PI3KI as a driver of cell proliferation, inhibitors have been actively sought as potential chemotherapeutic agents for cancer.

In pursuit of novel anti-cancer drugs, and equally in seeking drugs to prevent or ameliorate Alzheimer 's and other age-dependent diseases, potential therapeutic benefits of PI3KI inhibitors have been overshadowed by the virtual certainty that they would also be detrimental to stem cell niches.

This concern has motivated our search for PIP3-binding proteins as alternative targets downstream of PI3KI.

Among these, AKT is believed to drive most of the proliferative effects of PI3K, whereas RAD50, CAND1, FAT2 and TCT1 constitute novel targets that may preserve survival benefits of PI3KI disruption, uncoupled from blockage of cell proliferation.

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DOI - https://doi.org/10.18632/oncotarget.10549

Full text - https://www.oncotarget.com/article/10549/text/

Correspondence to - Robert J. Shmookler Reis - rjsr@uams.edu and Srinivas Ayyadevara - AyyadevaraSrinivas@uams.edu

Keywords - phosphatidylinositol 3-kinase, phosphatidylinositol 3,4,5-triphosphate (PIP3), longevity, oxidative stress resistance, protein aggregation