PXD013923

PXD013923 is an original dataset announced via ProteomeXchange.

Title	Global view of the RAF-MEK-ERK module and its immediate downstream effectors
Description	Small molecule inhibitors of BRAF and MEK have proven effective at inhibiting tumor growth in melanoma patients, however this efficacy is limited due to the almost universal development of drug resistance. To provide advanced insight into the signaling responses that occur following kinase inhibition we have performed quantitative (phospho)-proteomics of human melanoma cells treated with either Dabrafenib, a BRAF inhibitor; Trametinib, a MEK inhibitor or SCH772984, an ERK inhibitor. Over nine experiments we identified 7827 class I phosphosites on 4960 proteins. This included 54 phosphorylation sites that were significantly down-modulated after exposure to all three inhibitors, 34 of which have not been previously reported. Functional analysis of these novel ERK targets identified roles for them in GTPase activity and regulation, apoptosis and cell-cell adhesion. Comparison of the results presented here with previously reported phosphorylation sites downstream of ERK showed a limited degree of overlap suggesting that ERK signaling responses may be highly cell line and cue specific. In addition we identified 26 phosphorylation sites that were only responsive to Dabrafenib. We provide further orthogonal experimental evidence for 3 of these sites in human embryonic kidney cells over-expressing BRAF as well as further computational insights using KinomeXplorer. The validated phosphorylation sites were found to be involved in actin regulation, which has been proposed as a novel mechanism for inhibiting resistance development. These results would suggest that the linearity of the BRAF-MEK-ERK pathway is at least context dependent.
HostingRepository	PRIDE
AnnounceDate	2019-11-12
AnnouncementXML	Submission_2019-11-11_16:39:39.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	cristina santini
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-05-20 02:49:08	ID requested
⏵ 1	2019-11-11 16:39:40	announced

Santini CC, Longden J, Schoof EM, Simpson CD, Jeschke GR, Creixell P, Kim J, Wu X, Turk BE, Rosen N, Poulikakos PI, Linding R, Global view of the RAF-MEK-ERK module and its immediate downstream effectors. Sci Rep, 9(1):10865(2019) [pubmed]

submitter keyword: A375, BRAFV600E, BRAF, V600E, melanoma, phosphosites, Dabrafenib, RAF, inhibitor, Trametinib, MEK, ERK, SCH772984

Rune Linding
contact affiliation	Humboldt University of Berlin
contact email	linding@lindinglab.org
lab head
cristina santini
contact affiliation	University of Denmark
contact email	ccsantini@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD013923
     1. Label: PRIDE project
     2. Name: Global view of the RAF-MEK-ERK module and its immediate downstream effectors