PXD009662

PXD009662 is an original dataset announced via ProteomeXchange.

Title	Time resolved quantitative phospho-tyrosine analysis reveals Bruton’s Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors
Description	Granulocyte-colony stimulating factor receptor (G-CSFR) controls myeloid progenitor proliferation and differentiation to neutrophils. Mutations in CSF3R (encoding G-CSFR) have been reported in patients with chronic neutrophilic leukemia (CNL) and acute myeloid leukemia (AML); however, despite years of research, the malignant downstream signaling of the mutated G-CSFRs is not well understood. Here, we utilized a quantitative phospho-tyrosine analysis to generate a comprehensive signaling map of G-CSF induced tyrosine phosphorylation in the normal versus mutated (proximal: T618I and truncated: Q741x) G-CSFRs. Unbiased clustering and kinase enrichment analysis identified rapid induction of phospho-proteins associated with endocytosis by the wild-type G-CSFR only; while G-CSFR mutants showed abnormal kinetics of canonical STAT3, STAT5 and MAPK phosphorylation, and aberrant activation of Bruton’s Tyrosine Kinase (Btk). Mutant-G-CSFR-expressing cells displayed enhanced sensitivity (5-fold lower IC50) for Ibrutinib-based chemical inhibition of Btk. Finally, primary murine progenitor cells from G-CSFR-d715x knock-in mice validate activation of Btk by the mutant receptor, and display enhanced sensitivity to Ibrutinib. Together, these data demonstrate the strength of unsupervised proteomics analyses in dissecting oncogenic pathways, and suggest repositioning Ibrutinib for therapy of myeloid leukemia bearing CSF3R mutations.
HostingRepository	PRIDE
AnnounceDate	2018-07-11
AnnouncementXML	Submission_2019-06-17_03:26:55.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Pankaj Dwivedi
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2018-05-03 02:31:39	ID requested
1	2018-07-11 08:05:41	announced
⏵ 2	2019-06-17 03:26:57	announced	Updated publication reference for PubMed record(s): 29977015, 30967555.

Dwivedi P, Muench DE, Wagner M, Azam M, Grimes HL, Greis KD, Time resolved quantitative phospho-tyrosine analysis reveals Bruton's Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors. Leukemia, 33(1):75-87(2019) [pubmed]

Dwivedi P, Muench DE, Wagner M, Azam M, Grimes HL, Greis KD, Phospho serine and threonine analysis of normal and mutated granulocyte colony stimulating factor receptors. Sci Data, 6(1):21(2019) [pubmed]

curator keyword: Biological

submitter keyword: AML, CNL, IBRUTINIB, RUXOLITINIB, SILAC, PHOSPHOPROTEOMICS, LC-MS/MS

Kenneth Greis
contact affiliation	Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45267
contact email	greiskd@ucmail.uc.edu
lab head
Pankaj Dwivedi
contact affiliation	University of Cincinnati
contact email	dwivedpj@mail.uc.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/2018/07/PXD009662

PRIDE project URI

• PRIDE
  1. PXD009662
     1. Label: PRIDE project
     2. Name: Time resolved quantitative phospho-tyrosine analysis reveals Bruton’s Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors