PXD018296 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | mTORC1 and mTORC2 converge on the Arp2/3 complex to promote KrasG12D-induced acinar-to-ductal metaplasia and early pancreatic carcinogenesis |
Description | Oncogenic KrasG12D, a driver mutation of pancreatic ductal adenocarcinoma (PDAC), induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). Here, we show that both functional complexes of mTOR (mechanistic target of rapamycin kinase, mTORC1 and mTORC2) are specifically activated in ADM. Murine models uncover that mTORC1 and mTORC2 cooperate to promote KrasG12D-driven ADM development. Proteomic analyses identify Arp2/3 complex, an actin nucleator, as the common downstream effector: mTORC1 is responsible for the protein synthesis of Rac1 and Arp3 while mTORC2 promotes the Arp2/3 complex activity via Akt/Rac1 signalling. Genetic ablation of Arp2/3 complex completely arrests KrasG12D-driven ADM development. The Arp2/3 complex-mediated y-branching of actin network promotes the basolateral spread of filamentous actin, which is indispensable for acinar cells-initiated carcinogenesis. Induced by oncogenic KrasG12D, ADM is a metaplastic phenotype of acinar cells that requires extensive actin rearrangements. mTORC1 and mTORC2, downstream targets of KrasG12D, have well-established oncogenic functions in PDAC development. The actin-related protein 2/3 (Arp2/3) complex is the first identified actin nucleator. Regarded as textbook knowledge, it is activated by EGFR/Rac1 signalling to promote the polymerisation of branched actin filaments from pre-existing filaments in numerous biological contexts. Hereby, we identify that mTORC1 and mTORC2 attain a dual, yet non-redundant, regulatory role in promoting Arp2/3 complex function, which is responsible for generating basolateral filamentous actin in ADM. Thus, the role of Arp2/3 complex fills up the missing gap between putative oncogenic signals and actin dynamics underlying PDAC initiation. |
HostingRepository | PRIDE |
AnnounceDate | 2021-01-07 |
AnnouncementXML | Submission_2021-01-07_00:14:44.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Christina Ludwig |
SpeciesList | scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; |
ModificationList | monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive HF |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2020-03-30 23:53:51 | ID requested | |
⏵ 1 | 2021-01-07 00:14:44 | announced | |
Publication List
Zhao Y, Schoeps B, Yao D, Zhang Z, Schuck K, Tissen V, J, ä, ger C, Schlitter AM, van der Kammen R, Ludwig C, D'Haese JG, Raulefs S, Maeritz N, Shen S, Zou X, Kr, ü, ger A, Kleeff J, Michalski CW, Friess H, Innocenti M, Kong B, -Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis. Gastroenterology, 160(5):1755-1770.e17(2021) [pubmed] |
Keyword List
submitter keyword: pancreatic cancer |
ADM |
Arp2/3 complex |
mTOR |
actin rearrangement |
Contact List
Christina Ludwig |
contact affiliation | Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS) Technical University Munich (TUM) Gregor-Mendel-Straße 4 85354 Freising GERMANY |
contact email | tina.ludwig@tum.de |
lab head | |
Christina Ludwig |
contact affiliation | TU Munich |
contact email | tina.ludwig@tum.de |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD018296
- Label: PRIDE project
- Name: mTORC1 and mTORC2 converge on the Arp2/3 complex to promote KrasG12D-induced acinar-to-ductal metaplasia and early pancreatic carcinogenesis