Mutant GNAS drives pancreatic tumorigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism
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ABSTRACT:
PROVIDER: PRJNA471090 | ENA |
REPOSITORIES: ENA
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Project description:Proteome maps were generated for mouse KGC pancreatic tumor organoid lines expressing doxycycline-inducible constitutively-active mutant GNAS (GNASR201C). The organoids were analyzed in the absence (ctrl) or presence (induced) of doxycycline. Two models, KGC Line-1 (line1) and Line-2 (line2), were analyzed in two separate experiments, 1 and 2. Proteome maps were generated using multiplexed proteomics using TMT10plex technology. Mass spectrometry was done on an Orbitrap Fusion using the SPS-MS3 method. TMT labeling was done as follows: experiment 1, line1_induced_replicate1 (126), line1_ctrl_replicate1 (127n), line2_induced_replicate1 (127c), line2_ctrl_replicate1 (128n), line1_induced_replicate2 (128c), line1_ctrl_replicate2 (129n), line2_induced_replicate2 (129c), line2_ctrl_replicate2 (130c); experiment 2, line1_induced_replicate1 (126), line1_induced_replicate2 (127n), line1_induced_replicate3 (127c), line1_ctrl_replicate1 (128n), line1_ctrl_replicate2 (128c), line1_ctrl_replicate3 (129n), line2_induced_replicate1 (129c), line2_induced_replicate2 (130n), line2_ctrl_replicate1 (130c), line2_ctrl_replicate2 (131).
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Project description:Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, inhibits SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many new PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC cancer stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover novel targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.
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Project description:When exploring the role of Gαs and β-arrestin in nuclear transcriptional programs downstream from β2-adrenergic receptor (β2AR), we noticed a dearth of information on PKA-regulated genes sets. Thus, we first used the tetracycline-regulated expression of wild type PKA Cα subunit in HEK293 cells to develop a PKA signature. This approach revealed multiple PKA-regulated genes, including well known PKA downstream transcriptional targets, such as PCK1 and FOS, and many new PKA transcriptional targets whose underlying mechanism can now be explored.
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