Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice
Open accessAbstract
The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer’s disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.
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Inhibition of the Hippo pathway releases KIBRA from its association with LATS1/2, thus enhancing AMPA-receptor-mediated transmission.
“a recent study has demonstrated that inhibition of the Hippo pathway releases KIBRA from its association with LATS1/2, thus enhancing AMPA‐receptor‐mediated transmission (Stepan et al. 2024)”
From The Serine/Threonine Kinase <scp>NDR2</scp> Regulates Integrin Signaling, Synapse Formation, and Synaptic Plasticity in the Hippocampus (2025) · cites this paper as Stepan et al. 2024
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Cites
Hippo pathway in organ size control, tissue homeostasis, and cancer
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The AMPA Receptor Code of Synaptic Plasticity
Diering, G. H., & Huganir, R. L. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.018 · Cited by 844 · cited 1× · see citing works
“…the strength of synaptic transmission, which are mediated by various molecular mechanisms, including the number, spatial organization, and function of α - amino- 3- hydroxy- 5- methyl- 4-isoxazolepropionic acid receptors (AMPARs) and their associated proteins in the postsynaptic membrane ( 1 , 2 ).”
BackgroundRegulation of AMPA receptor lateral movements
Borgdorff, A. J., & Choquet, D. (2002) · Nature · doi:10.1038/nature00780 · Cited by 542 · see citing works
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KIBRA Regulates Hippo Signaling Activity via Interactions with Large Tumor Suppressor Kinases
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del Ángel, M., Tsutiya, A., Hayani, H., Madencioglu, D., Kul, E., Caliskan, G., Demiray, Y. E., Dityatev, A., & Stork, O. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70094 · Cited by 1 · see citing works
“Moreover, a recent study has demonstrated that inhibition of the Hippo pathway releases KIBRA from its association with LATS1/2, thus enhancing AMPA- receptor-mediated transmission (Stepan et al. 2024).”
- Authors
- Stepan, J., Heinz, D. E., Dethloff, F., Wiechmann, S., Martinelli, S., Hafner, K., Ebert, T., Junglas, E., Häusl, A. S., Pöhlmann, M. L., Jakovcevski, M., Pape, J. C., Zannas, A. S., Bajaj, T., Hermann, A., Ma, X., Pavenstädt, H., Schmidt, M. V., Philipsen, A., Turck, C. W., Deussing, J. M., Rammes, G., Robinson, A. C., Payton, A., Wehr, M. C., Stein, V., Murgatroyd, C., Kremerskothen, J., Kuster, B., Wotjak, C. T., & Gassen, N. C.
- Affiliations
- Paracelsus Medical University (AT)
- University Hospital Bonn (DE)
- Max Planck Institute of Psychiatry (DE)
- German Cancer Research Center (DE)
- University of North Carolina at Chapel Hill (US)
- University Hospital Münster (DE)
- LMU Klinikum (DE)
- Kunming Institute of Zoology (CN)
- TUM Klinikum (DE)
- Manchester Academic Health Science Centre (GB)
- University of Manchester (GB)
- University of Bonn (DE)
- Department of Life Sciences, Manchester Metropolitan University, Manchester M15 6BH, UK.
- Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany.
- Boehringer Ingelheim (Germany) (DE)
- Corresponding author
- Stepan, Jens
- Gassen, Nils C.
- ORCID
- Stepan, Jens
- Heinz, Daniel E.
- Dethloff, Frederik
- Wiechmann, Svenja
- Martinelli, Silvia
- Häusl, Alexander S.
- Pöhlmann, Max L.
- Jakovcevski, Mira
- Pape, Julius C.
- Zannas, Anthony S.
- Bajaj, Thomas
- Ma, Xiao
- Pavenstädt, Hermann
- Schmidt, Mathias V.
- Philipsen, Alexandra
- Turck, Christoph W.
- Deussing, Jan M.
- Rammes, Gerhard
- Robinson, Andrew C.
- Payton, Antony
- Wehr, Michael C.
- Stein, Valentin
- Kuster, Bernhard
- Wotjak, Carsten T.
- Gassen, Nils C.
- Venue
- Science Signaling
- Published
- 2024-04-30
- Volume
- 17
- Issue
- 834
- Pages
- eadj6603-eadj6603
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- OpenAlex
- W4396528250
- Cited by
- 20
- References
- 8
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 2
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by)
- e-space (Manchester Metropolitan University) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- Hippo signaling pathway, WWC1, LATS1/2, MST1/2, AMPA receptors, synaptic plasticity, long-term memory, kinase inhibition, protein-protein interaction, hippocampal neurons, Alzheimer's disease, nootropic drugs, synaptic transmission
- MeSH terms
- Hippo Signaling Pathway, Serine-Threonine Kinase 3, Hippo Kinases, Alzheimer Disease, Animals, Hippocampus, Humans, Male, Memory, Mice, Inbred C57BL, Neuronal Plasticity, Neurons, Phosphoproteins, Phosphorylation, Signal Transduction, Hepatocyte Growth Factor, Protein Serine-Threonine Kinases, Receptors, AMPA, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, Mice
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