ArticleMolecular psychiatry2020
A kinome-wide RNAi screen identifies ERK2 as a druggable regulator of Shank3 stability.
Article in Molecular psychiatry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 35 citations in OpenAlex.
- Review
- Shank3 related oligodendrocyte alterations in autism are restored by Erk pathway inhibition.Molecular psychiatry · 2026Article
- SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers.Nature communications · 2024Article
- Pharmacological modulation of developmental and synaptic phenotypes in human SHANK3 deficient stem cell-derived neuronal models.Translational psychiatry · 2024Article
- Shank3 deficiency elicits autistic-like behaviors by activating p38α in hypothalamic AgRP neurons.Molecular autism · 2024Article
- Targeting Shank3 deficiency and paresthesia in autism spectrum disorder: A brief review.Frontiers in molecular neuroscience · 2023Review
- SHANK family on stem cell fate and development.Cell death & disease · 2022Review
- A perspective on molecular signalling dysfunction, its clinical relevance and therapeutics in autism spectrum disorder.Experimental brain research · 2022Review
- Association of SHANK Family with Neuropsychiatric Disorders: An Update on Genetic and Animal Model Discoveries.Cellular and molecular neurobiology · 2022Review
- A bidirectional switch in the Shank3 phosphorylation state biases synapses toward up- or downscaling.eLife · 2022Article
- Utilizing Genomically Targeted Molecular Data to Improve Patient-Specific Outcomes in Autism Spectrum Disorder.International journal of molecular sciences · 2022Article
- G-alpha interacting protein interacting protein, C terminus 1 regulates epileptogenesis by increasing the expression of metabotropic glutamate receptor 7.CNS neuroscience & therapeutics · 2022Article
- Emerging strategies for the genetic dissection of gene functions, cell types, and neural circuits in the mammalian brain.Molecular psychiatry · 2022Review
- Degradome-focused RNA interference screens to identify proteases important for breast cancer cell growth.Frontiers in oncology · 2022Article
- Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications.Journal of neurodevelopmental disorders · 2021Review
- Genomics as a Clinical Decision Support Tool: Successful Proof of Concept for Improved ASD Outcomes.Journal of personalized medicine · 2021Article
- Autism-associatedeLife · 2021Article
- Increased ribosomal protein levels and protein synthesis in the striatal synaptosome of Shank3-overexpressing transgenic mice.Molecular brain · 2021Article
- Article
- Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts.Frontiers in molecular neuroscience · 2020Review
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
Abstract
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 itself might be more fruitful than correcting pathways that function downstream of it for treatment of disorders caused by alterations in SHANK3 dosage. To identify upstream regulators of Shank3 abundance, we performed a kinome-wide siRNA screen and identified multiple kinases that potentially regulate Shank3 protein stability. 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. Altogether, 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.