PXD021836

PXD021836 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2020-10-05 04:22:47	ID requested
⏵ 1	2021-08-05 03:15:14	announced

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]

submitter keyword: AKT inhibitor, phosphoproteomics, kinobeads

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

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PRIDE project URI

• PRIDE
  1. PXD021836
     1. Label: PRIDE project
     2. Name: Chemical phosphoproteomics sheds new light on the targets and modes of action of AKT inhibitors