ArticleNature cell biology2017
SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras.
Article in Nature cell biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
76 citing papers in PubMed, 134 citations in OpenAlex.
- SIMLINK enables accurate variant pathogenicity prediction through modeling the gene-variant-feature association structure.Bioinformatics (Oxford, England) · 2026Article
- Region-specific microglial alterations in the acoustic startle circuit in Shank3 mice.Biochemistry and biophysics reports · 2026Article
- Diverging transposon activity among polar bear sub-populations inhabiting different climate zones.Mobile DNA · 2025Article
- Integrin β1 activity controls colony morphology during human pluripotent stem cell state transitions.Stem cell reports · 2025Article
- Divergent Functions of Rap1A and Rap1B in Endothelial Biology and Disease.International journal of molecular sciences · 2025Review
- Mechanochemistry: Fundamental Principles and Applications.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Scaffold Proteins in Fibrotic Diseases of Visceral Organs.Biomolecules · 2025Review
- Luminescent sensing of conformational integrin activation in living cells.Cell reports · 2025Article
- Talin, a Rap1 effector for integrin activation at the plasma membrane, also promotes Rap1 activity by disrupting sequestration of Rap1 by SHANK3.Journal of cell science · 2025Article
- SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers.Nature communications · 2024Article
- An N-terminal and ankyrin repeat domain interactome of Shank3 identifies the protein complex with the splicing regulator Nono in mice.Genes to cells : devoted to molecular & cellular mechanisms · 2024Article
- Structural deficits in key domains of Shank2 lead to alterations in postsynaptic nanoclusters and to a neurodevelopmental disorder in humans.Molecular psychiatry · 2024Article
- Focal adhesions contain three specialized actin nanoscale layers.Nature communications · 2024Article
- Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium.Molecular psychiatry · 2024Article
- The Shank/ProSAP N-Terminal (SPN) Domain of Shank3 Regulates Targeting to Postsynaptic Sites and Postsynaptic Signaling.Molecular neurobiology · 2024Article
- Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease.Frontiers in molecular neuroscience · 2024Review
- Mapping proteomic composition of excitatory postsynaptic sites in the cerebellar cortex.Frontiers in molecular neuroscience · 2024Article
- Spatial Mechano-Signaling Regulation of GTPases through Non-Degradative Ubiquitination.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Article
- Stress-mediated dysregulation of the Rap1 small GTPase impairs hippocampal structure and function.iScience · 2023Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
Abstract
SHANK3, a synaptic scaffold protein and actin regulator, is widely expressed outside of the central nervous system with predominantly unknown function. Solving the structure of the SHANK3 N-terminal region revealed that the SPN domain is an unexpected Ras-association domain with high affinity for GTP-bound Ras and Rap G-proteins. The role of Rap1 in integrin activation is well established but the mechanisms to antagonize it remain largely unknown. Here, we show that SHANK1 and SHANK3 act as integrin activation inhibitors by sequestering active Rap1 and R-Ras via the SPN domain and thus limiting their bioavailability at the plasma membrane. Consistently, SHANK3 silencing triggers increased plasma membrane Rap1 activity, cell spreading, migration and invasion. Autism-related mutations within the SHANK3 SPN domain (R12C and L68P) disrupt G-protein interaction and fail to counteract integrin activation along the Rap1-RIAM-talin axis in cancer cells and neurons. Altogether, we establish SHANKs as critical regulators of G-protein signalling and integrin-dependent processes.
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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.