PXD028167

PXD028167 is an original dataset announced via ProteomeXchange.

Title	S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions
Description	Functioning as a master kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) plays a fundamental role in phosphorylating and activating protein kinases A, B and C (AGC) family kinases, including AKT. However, upstream regulation of PDK1 remains largely elusive. Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. Mechanistically, S6K1-mediated phosphorylation of PDK1 augments its interaction with 14-3-3 adaptor protein and homo-dimerization, subsequently dissociating PDK1 from phosphatidylinositol 3,4,5 triphosphate (PIP3) and retarding its interaction with AKT. Pathologically, tumor patient-associated PDK1 mutations, either attenuating S6K1-mediated PDK1 phosphorylation or impairing PDK1 interaction with 14-3-3, result in elevated AKT kinase activity and oncogenic functions. Taken together, our findings not only unravel a delicate feedback regulation of AKT signaling via S6K1-mediated PDK1 phosphorylation, but also highlight the potential strategy to combat mutant PDK1-driven cancers.
HostingRepository	iProX
AnnounceDate	2021-08-27
AnnouncementXML	Submission_2022-10-21_02:41:32.935.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jianping Guo
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-08-27 00:38:36	ID requested
1	2021-08-27 00:38:49	announced
⏵ 2	2022-10-21 02:41:33	announced	2022-10-21: Update publication information.

Jiang Q, Zhang X, Dai X, Han S, Wu X, Wang L, Wei W, Zhang N, Xie W, Guo J, S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions. Nat Commun, 13(1):1548(2022) [pubmed]

submitter keyword: PDK1, S6K

Jianping Guo
contact affiliation	Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University
contact email	guojp6@mail.sysu.edu.cn
lab head
Jianping Guo
contact affiliation	Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University
contact email	guojp6@mail.sysu.edu.cn
dataset submitter

iProX dataset URI