In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5565-5565
Abstract:
Functional phosphoproteomics is applied to gain the molecular insights into oncogenic RAS-mediated signaling pathway in lung adenocarcinoma. By means of immobilized metal affinity chromatography, mass spectrometry and a robust label-free quantitative system, we compared the phosphorylation profiles of five cell lines including immortalized normal human bronchial epithelial cells (HBECs) (wt KRAS), 3KTR (KRASG12V-transfected HBECs), A549 (KRASG12D), H322 (amplified KRAS), and H1299 (NRASQ61K). This resulted in the quantification of 1508 phosphorylation events and detection of regulated events across the cell lines. NetworKIN analysis of 2-fold regulated events (n=77) induced by oncogenic RAS in HBECs revealed 20 novel site-specific phosphorylation targets of MAP kinases. By browsing through STRING database, we identified 44 known substrates of MAP kinases in the interactome of phosphoproteins in this study. Further analysis of the site-specific upstream kinases of regulated phosphorylation events revealed the significant increase in basal kinases such as PAK, AKT/PKB and PKA in H1299 (large cell carcinoma) relative to A549 and H322 (adenocarcinoma). This increase in basal kinases may in-turn modulate the output of RAS-mediated MAPK signaling in large cell carcinoma cells (H1299). Supporting these results, majority of the regulated phosphorylation events (n=77) including MAPK, identified in HBECs expressing oncogenic RAS, were also differentially regulated in A549 and H322 but not in H1299. Further, inferring pathway signatures by integrating expression data of phosphorylation profiles to pathway interaction database, revealed the activation of MAPK signaling in 3KTR, A549 and H322 but not in H1299, whereas the activation of AKT and inactivation of mTOR signaling in H1299. Taken together, we demonstrate the phosphorylation targets, molecular regulation, and pathway activity signatures of onogenic RAS-mediated MAPK signaling in lung adenocarcinoma. Furthermore, the method introduced here to infer the pathway signatures is adaptable for future studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5565.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-5565
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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