Abstract Details

Title A kinome-wide RNAi screen identifies ERK2 as a druggable regulator of Shank3 stability

Topic Child Neurology and Developmental Neurology

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 7-030

Objective The objective of this work is to identify therapeutic entry points for an autism spectrum disorder, Phelan-McDermid syndrome.

Background Neurons are sensitive to changes in the dosage of many genes, especially those regulating synaptic functions. Haploinsufficiency of SHANK3 causes Phelan-McDermid syndrome and autism, whereas duplication of the same gene leads to SHANK3 duplication syndrome, a disorder characterized by neuropsychiatric phenotypes including hyperactivity and bipolar disorder as well as epilepsy. We recently demonstrated the functional modularity of Shank3, which suggests that normalizing levels of Shank3 itselfmight be more fruitful than correcting pathways that function downstream of it for treatment of disorders caused by alterations in SHANK3 dosage.

Design/Methods To identify upstream regulators of Shank3 abundance, we performed a kinome-wide siRNA screen and identified multiple kinases that potentially regulate Shank3 protein stability.

Results Interestingly, we discovered that several kinases in the MEK/ERK2 pathway destabilize Shank3 and that genetic deletion and pharmacological inhibition of ERK2 increases Shank3 abundance in vivo. Mechanistically, we show that ERK2 binds Shank3 and phosphorylates it at three residues to promote its poly-ubiquitination-dependent degradation.

Conclusions

Together, our findings uncover a druggable pathway as a potential therapeutic target for disorders with reduced SHANK3 dosage, provide a rich resource for studying Shank3 regulation, and demonstrate the feasibility of this approach for identifying regulators of dosage-sensitive genes.

Authors/Disclosures
Jimmy Holder, MD (BCM) PRESENTER	Dr. Holder has received personal compensation in the range of $0-$499 for serving as a Consultant with Stoke Pharmaceutical.
	No disclosure on file

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