PXD001101 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Identifying novel targets of oncogenic EGF receptor signaling in lung cancer through global phosphoproteomics |
Description | Mutations in the epidermal growth factor receptor (EGFR) kinase domain occur in 10-30% of lung adenocarcinoma. Leucine to arginine substitution at amino acid position 858 (L858R) accounts for around 50% of EGFR-tyrosine kinase inhibitor (TKI) sensitizing mutations. A second site mutation in the gatekeeper residue (T790M) accounts for around 60% of acquired resistance to EGFR-TKIs. We sought to identify the immediate direct and indirect targets of these mutant EGFRs in lung adenocarcinoma and their modulation by erlotinib, the first generation, and most widely used EGFR-directed TKI. We undertook stable isotope labeling of amino acids in cell culture (SILAC), phosphopeptide enrichment, and quantitative mass spectrometry to identify dynamic changes of phosphorylation downstream of mutant EGFRs in lung adenocarcinoma cells harboring L858R or L858R/T790M mutations and their modulation by erlotinib inhibition. Phosphorylation at the majority of phosphosites identified exhibited no change upon either EGF stimulation or erlotinib inhibition. Only around 7% of phosphosites identified and quantified showed increased phosphorylation upon EGF stimulation in either cell line. However, while phosphorylation at 61% of these phosphosites decreased upon erlotinib inhibition in the TKI sensitive H3255 cells, only 24% of such sites exhibited decreased phosphorylation upon erlotinib inhibition in the TKI resistant H1975 cells. Top canonical pathways that were inhibited upon erlotinib treatment in sensitive cells, but not the resistant cells include EGFR, Insulin receptor, HGF, MAPK, mTOR, p70S6K and JAK/STAT signaling. We identified phosphosites in proteins of the autophagy network, such as ULK1 (S623) that is constitutive phosphorylated in these lung adenocarcinoma cells, but phosphorylation is inhibited upon erlotinib treatment in sensitive cells, but not resistant cells. Finally, kinase-substrate prediction analysis from our data indicated that substrates of basophilic kinase families, AGC, CAMK and STE were significantly enriched and those of proline directed kinase families, CMGC and CK were significantly depleted among substrates that exhibit increased phosphorylation upon EGF stimulation and reduced phosphorylation upon TKI inhibition. This is the first study to date to examine global phosphorylation changes upon erlotinib treatment of lung adenocarcinoma cells and results from this study provide new insights into signaling downstream of mutant EGFRs in lung adenocarcinoma. |
HostingRepository | PRIDE |
AnnounceDate | 2015-01-30 |
AnnouncementXML | Submission_2015-01-30_06:36:49.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Udayan Guha |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | phosphorylated residue |
Instrument | LTQ Orbitrap; LTQ Orbitrap Elite |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2014-06-30 13:42:17 | ID requested | |
1 | 2015-01-30 06:03:51 | announced | |
⏵ 2 | 2015-01-30 06:36:50 | announced | Web service failed to respond, now attempting again. |
Publication List
Zhang X, Belkina N, Jacob HK, Maity T, Biswas R, Venugopalan A, Shaw PG, Kim MS, Chaerkady R, Pandey A, Guha U, Identifying novel targets of oncogenic EGF receptor signaling in lung cancer through global phosphoproteomics. Proteomics, 15(2-3):340-55(2015) [pubmed] |
Keyword List
curator keyword: Biomedical |
submitter keyword: EGFR, NSCLC, adenocarcinoma, TKI, phosphoproteomics |
Contact List
Udayan Guha |
contact affiliation | Thoracic and GI Oncology Branch, NCI, NIH |
contact email | udayan.guha@nih.gov |
lab head | |
Udayan Guha |
contact affiliation | NCI/NIH |
contact email | udayan.guha@nih.gov |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD001101
- Label: PRIDE project
- Name: Identifying novel targets of oncogenic EGF receptor signaling in lung cancer through global phosphoproteomics