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Profiling of mTORC1 signaling in rat liver using mass spectrometry

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  1. Tez No: 401299
  2. Yazar: GÖKHAN DEMİRKAN
  3. Danışmanlar: DR. PHILIP A. GRUPPUSO
  4. Tez Türü: Doktora
  5. Konular: Genetik, Biyokimya, Genetics, Biochemistry
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2011
  8. Dil: İngilizce
  9. Üniversite: Brown Unıversıty
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Belirtilmemiş.
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: Belirtilmemiş.

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Özet (Çeviri)

Our understanding of signaling networks in the physiological context of an organism remains limited, partly due to the technical challenge of identifying serine/threonine phosphorylated peptides from complex tissue samples. We have developed a phosphoproteomic strategy to purify, enrich and identify phosphopeptides in rat liver homogenates. We focused on signaling through the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which is at the center of a nutrient- and growth factor-responsive cell signaling network. Using the immunosuppressant and anticancer drug rapamycin, the only known target of which is mTORC1, we characterized signaling in liver from rats in which the complex was maximally activated using the model of refeeding following 48 hr of starvation. Through a combination of protein and peptide fractionation methods, TiO2 affinity purification of phosphopeptides and mass spectrometry, we reproducibly identified and quantified over four thousand phosphopeptides. Along with 5 known rapamycin-sensitive phosphorylation events, we identified 77 new rapamycin-sensitive candidate phosphorylation sites. Among these were PRAS40 (an Akt substrate), gephyrin, and AMP kinase 2. We observed similar proportions of enhanced and reduced phosphorylation in response to rapamycin. Gene ontology analysis revealed over-representation of mTORC1 sites and translation control sites in rapamycin-sensitive candidates list. These results support the purported physiological role of mTORC1 signaling while identifying new targets within this important signaling network.Protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase that interacts with a wide array of proteins that regulate its activity, influence substrate specificity, determine intracellular localization and serve as substrates for dephosphrylation. PP2A is involved in many signal transduction pathways. Among them is that involving the mTOR. Through the use of microcystin (MC) affinity purification and MS/MS sequencing, we identified a large number of PP2A subunits and interacting proteins in vivo. Although our preliminary assessment lacked any obvious effects of rapamycin on PP2A complexes, we demonstrated the validity and usefulness of MC affinity purification approach and identified a large number of novel post-translational modifications (PTMs) in both the catalytic and regulatory subunits of PP2A.

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