PXD021836 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Chemical phosphoproteomics sheds new light on the targets and modes of action of AKT inhibitors |
Description | Due to its important roles in oncogenic signaling, AKT has been subject to extensive drug discovery efforts leading to small molecule inhibitors investigated in advanced clinical trials. To better understand how these drugs exert their therapeutic effects at the molecular level, we combined chemoproteomic target affinity profiling using kinobeads and phosphoproteomics to analyses the five clinical AKT inhibitors AZD5363 (Capivasertib), GSK2110183 (Afuresertib), GSK690693, Ipatasertib and MK-2206 in BT-474 breast cancer cells. Kinobead profiling identified between four and 29 nanomolar targets for these compounds and showed that AKT1 and AKT2 were the only common targets. Similarly, measuring the response of the phosphoproteome to the same inhibitors identified ~1,700 regulated phosphorylation sites, 276 of which were perturbed by all five compounds. This analysis expanded the known AKT signaling network by 119 phosphoproteins that may represent direct or indirect targets of AKT. Within this new network, 41 regulated phosphorylation sites harbor the AKT substrate motif and recombinant kinase assays validated 16 as novel AKT substrates. These included CEP170 and FAM83H, suggesting a regulatory function of AKT in mitosis and cytoskeleton organization. In addition, a specific phosphorylation pattern on the ULK1-FIP200-ATG13-VAPB complex was found to determine the active state of ULK1, leading to elevated autophagy in response to AKT inhibition. |
HostingRepository | PRIDE |
AnnounceDate | 2021-08-05 |
AnnouncementXML | Submission_2021-08-05_03:15:13.580.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Svenja Wiechmann |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | phosphorylated residue |
Instrument | Orbitrap Fusion Lumos; Orbitrap Fusion; LTQ Orbitrap Elite |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2020-10-05 04:22:47 | ID requested | |
⏵ 1 | 2021-08-05 03:15:14 | announced | |
Publication List
Wiechmann S, Ruprecht B, Siekmann T, Zheng R, Frejno M, Kunold E, Bajaj T, Zolg DP, Sieber SA, Gassen NC, Kuster B, Chemical Phosphoproteomics Sheds New Light on the Targets and Modes of Action of AKT Inhibitors. ACS Chem Biol, 16(4):631-641(2021) [pubmed] |
Keyword List
submitter keyword: AKT inhibitor, phosphoproteomics, kinobeads |
Contact List
Bernhard Kuster |
contact affiliation | Chair of Proteomics and Bioanalytics Technische Universitaet Muenchen Partner Site of the German Cancer Consortium Emil Erlenmeyer Forum 5 85354 Freising Germany |
contact email | kuster@tum.de |
lab head | |
Svenja Wiechmann |
contact affiliation | TU Munich, Proteomics and Bioanalytics |
contact email | svenja.wiechmann@tum.de |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD021836
- Label: PRIDE project
- Name: Chemical phosphoproteomics sheds new light on the targets and modes of action of AKT inhibitors