PXD030571

PXD030571 is an original dataset announced via ProteomeXchange.

Title	Inactivation of p21-Activated Kinase 2 (Pak2) Inhibits the Development of Nf2-Deficient Tumors by Restricting Downstream Hedgehog and Wnt Signaling
Description	Since loss of the NF2 tumor suppressor gene results in p21-activated kinase (Pak) activation, PAK inhibitors hold promise for the treatment of NF2-deficient tumors. To test this possibility, we asked if loss of Pak2, a highly expressed group I PAK member, affects the development of malignant mesothelioma in Nf2;Cdkn2a-deficient (NC) mice and the growth properties of NC mesothelioma cells in culture. In vivo, deletion of Pak2 resulted in a markedly decreased incidence and delayed onset of both pleural and peritoneal malignant mesotheliomas in NC mice. In vitro, Pak2 deletion decreased malignant mesothelioma cell viability, migration, clonogenicity, and spheroid formation. RNA-seq analysis demonstrated downregulated expression of Hedgehog and Wnt pathway genes in NC;Pak2-/- mesothelioma cells versus NC;Pak2+/+ mesothelioma cells. Targeting of the Hedgehog signaling component Gli1 or its target gene Myc inhibited cell viability and spheroid formation in NC;P+/+ mesothelioma cells. Kinome profiling uncovered kinase changes indicative of EMT in NC;Pak2-/- mesothelioma cells, suggesting that Pak2-deficient malignant mesotheliomas can adapt by reprogramming their kinome in the absence of Pak activity. The identification of such compensatory pathways offers opportunities for rational combination therapies to circumvent resistance to anti-PAK drugs.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:46:29.632.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joseph Testa
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-21 07:56:15	ID requested
1	2023-03-10 13:13:21	announced
⏵ 2	2023-11-14 07:46:30	announced	2023-11-14: Updated project metadata.

Sementino E, Kadariya Y, Cheung M, Menges CW, Tan Y, Kukuyan AM, Shrestha U, Karchugina S, Cai KQ, Peri S, Duncan JS, Chernoff J, Testa JR, Inactivation of p21-Activated Kinase 2 (Pak2) Inhibits the Development of Nf2-Deficient Tumors by Restricting Downstream Hedgehog and Wnt Signaling. Mol Cancer Res, 20(5):699-711(2022) [pubmed]

submitter keyword: Conditional knockout mice

malignant mesothelioma

Nf2 and Cdkn2a tumor suppressor genes

PAK

Hedgehog and Wnt signaling

cancer stem cells

Joseph R. Testa
contact affiliation	Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States
contact email	Joseph.Testa@fccc.edu
lab head
Joseph Testa
contact affiliation	Fox Chase Cancer Center
contact email	Joseph.Testa@fccc.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD030571

PRIDE project URI

• PRIDE
  1. PXD030571
     1. Label: PRIDE project
     2. Name: Inactivation of p21-Activated Kinase 2 (Pak2) Inhibits the Development of Nf2-Deficient Tumors by Restricting Downstream Hedgehog and Wnt Signaling