PXD050351

PXD050351 is an original dataset announced via ProteomeXchange.

Title	Targeting upstream Hippo-pathway kinases releases the scaffolder WWC1 to promote synaptic plasticity and long-term memory in mice
Description	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 hetero-protein complexes. However, genetic analysis suggests that the availability of WWC1 is constrained by its interaction with the Hippo kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction. A proteome-wide analysis of kinase inhibition in SH-SY5Y neuroblastoma cell line using the kinobead assay identified the upstream kinases MST1/2 as two major targets of the small molecule inhibitor XMU-MP1 (hereafter, MSTi)and Luteolin.Upon pharmacological inhibition of MST1/2 in male mice and human brain organoids WWC1 dissociated from LATS1/2, resulting in increased abundance of WWC1 in AMPAR complexes. Moreover, MSTi 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 ageing. Thus, blocking WWC1-LATS1/2 binding might be explored for development as cognitive enhancers.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:38:00.095.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tim Ebert
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-04 22:41:23	ID requested
1	2024-05-02 22:32:41	announced
⏵ 2	2024-10-22 06:38:00	announced	2024-10-22: Updated project metadata.

10.1126/SCISIGNAL.ADJ6603;

submitter keyword: kibra,WWC1, memory, kinobead, msti

Nils C Gassen
contact affiliation	RG Neurohomeostasis, Department of Psychiatry and Psychotherapy, University Hospital Bonn, Germany
contact email	Nils.Gassen@ukbonn.de
lab head
Tim Ebert
contact affiliation	University Hospital Bonn
contact email	tim.ebert@ukbonn.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050351
     1. Label: PRIDE project
     2. Name: Targeting upstream Hippo-pathway kinases releases the scaffolder WWC1 to promote synaptic plasticity and long-term memory in mice