PXD015188-1

PXD015188 is an original dataset announced via ProteomeXchange.

Title	Chemical and phosphoproteomics illuminate the cellular mode of action of AKT inhibitors
Description	Due to its key role in dysregulated cellular signaling in cancer, AKT has been subject to intense drug discovery efforts leading to small molecule inhibitors investigated in clinical trials, notably breast cancer. To shed more light on how these drugs exert their therapeutic effects, we integrated chemoproteomic target affinity profiling using the kinobeads approach and phosphoproteomics for the five designated AKT inhibitors AZD5363, GSK2110183, GSK690693, Ipatasertib and MK-2206 in breast cancer cells. Kinobead analysis identified between four and 29 nanomolar targets for these compounds and revealed 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 among which 276 were regulated by all drugs. This analysis expanded the AKT signaling network by 119 phosphoproteins that may represent direct or indirect targets of AKT. Within this network, we found 41 regulated phosphorylation sites bearing the AKT substrate motif and recombinant kinase assays validated 16 as novel AKT substrates. These included CEP170 and FAM83H, which suggest a direct regulatory function of AKT in mitosis and cytoskeleton organization. In addition, a specific phosphorylation pattern on ULK1, FIP200, ATG13 and VAPB was found to represent an active state of ULK1, leading to elevated autophagy in response to AKT inhibition. And last, secretome analysis of AKT inhibitor-treated cells identified STC2 as a putative blood-based drug response marker that may be tested in patients in the future.
HostingRepository	PanoramaPublic
AnnounceDate	2022-01-21
AnnouncementXML	Submission_2022-01-21_09:55:32.717.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Julia Mergner
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	Phospho; Label:13C(6)15N(2); Label:13C(6)15N(4)
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-08-27 16:14:12	ID requested
⏵ 1	2022-01-21 09:55:33	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, phosphorylation

Bernhard Kuster
contact affiliation	Chair of Proteomics and Bioanalytics Technische Universitaet Muenchen Partner Site of the German Cancer Consortium, Freising, Germany
contact email	kuster@tum.de
lab head
Julia Mergner
contact affiliation	Technical University of Munich
contact email	julia.mergner@tum.de
dataset submitter

Panorama Public dataset URI