Proteomics

Dataset Information

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High-throughput identification of FLT3 wild-type and mutant kinase substrate preferences and application to design of sensitive in vitro kinase assay substrates


ABSTRACT: Abnormalities in the FLT3 signaling pathway play an integral role in AML disease relapse and drug resistance. Developing new and specific FLT3 tyrosine kinase inhibitors for use in combination to induction therapy is an important step to reduce disease relapse and achieve clinical remission. To develop potent FLT3 TKI requires sensitive in vitro assay that depended on efficient FLT3 artificial substrates, which there are none reported for FLT3 WT and kinase variants. The kinase assay linked with phosphoproteomics was applied as a high throughput technique to increase the known FLT3 kinase substrates (WT, ITD and D835Y) that were used to identify the FLT3 kinase variant’s preferred kinase sequence using the KINATEST-ID substrate predictive pipeline. The identified substrate sequence was used to synthesize and validate pan-FLT3 artificial substrates to monitor in vitro kinase activity in the presence of clinically relevant FLT3 TKI.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Macrophage

DISEASE(S): Acute Leukemia

SUBMITTER: Minervo Perez  

LAB HEAD: Laurie L. Parker

PROVIDER: PXD011478 | Pride | 2019-01-07

REPOSITORIES: Pride

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Publications

High-throughput Identification of FLT3 Wild-type and Mutant Kinase Substrate Preferences and Application to Design of Sensitive <i>In Vitro</i> Kinase Assay Substrates.

Perez Minervo M   Blankenhorn John J   Murray Kevin J KJ   Parker Laurie L LL  

Molecular & cellular proteomics : MCP 20181212 3


Acute myeloid leukemia (AML) is an aggressive disease that is characterized by abnormal increase of immature myeloblasts in blood and bone marrow. The FLT3 receptor tyrosine kinase plays an integral role in hematopoiesis, and one third of AML diagnoses exhibit gain-of-function mutations in FLT3, with the juxtamembrane domain internal tandem duplication (ITD) and the kinase domain D835Y variants observed most frequently. Few FLT3 substrates or phosphorylation sites are known, which limits insight  ...[more]

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