PXD021748

PXD021748 is an original dataset announced via ProteomeXchange.

Title	A Unique Signaling Feedback Circuit Defines Interferon Responses in Myeloproliferative Neoplasms
Description	Type I interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and can also directly inhibit tumor growth. IFN is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFN therapy and others do not. We have identified and characterized a novel pathway involving PKC upstream of the kinase ULK1. Engagement of the Type I IFN receptor triggers PKC-dependent phosphorylation of ULK1 on serines 341 and 495, required for subsequent engagement of p38 MAPK that regulates transcription of IFN-stimulated genes and subsequent growth inhibitory responses. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from patients with MPNs in vitro, while increased levels of ULK1 and p38 MAPK correlate with clinical response to IFN therapy in MPN patients. IFN treatment also induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vivo, triggering a negative feedback loop that suppresses IFN responses. Both ROCK homologs are overexpressed in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid progenitors from MPN patients. Together, our results identify activation of the PKC-ULK1-p38 MAPK cascade as a key and essential component for the IFN-response, regulated by a feedback loop involving ROCK1/2. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPN patients.
HostingRepository	PRIDE
AnnounceDate	2022-01-10
AnnouncementXML	Submission_2022-01-10_13:10:18.498.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD021748
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Paul Thomas
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2020-09-30 00:02:11	ID requested
⏵ 1	2022-01-10 13:10:18	announced

Dataset with its publication pending

submitter keyword: interferon, neoplasm, ULK1, ROCK1, ROCK2

Leonidas C. Platanias
contact affiliation	Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
contact email	l-platanias@northwestern.edu
lab head
Paul Thomas
contact affiliation	Northwestern University
contact email	paul-thomas@northwestern.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD021748
     1. Label: PRIDE project
     2. Name: A Unique Signaling Feedback Circuit Defines Interferon Responses in Myeloproliferative Neoplasms